Emerging KRAS G12D inhibitor in the treatment of digestive system tumors: opportunities and challenges

Introduction

RAS proteins are small GTPases that act as molecular switches, cycling between an inactive GDP-bound state and an active GTP-bound state, thereby regulating cell proliferation, differentiation, and survival (1). They are encoded by three genes—HRAS, NRAS, and KRAS—among which KRAS is the most frequently mutated isoform in human cancers (2). Oncogenic mutations in KRAS reduce its intrinsic GTPase activity, leading to impaired GTP hydrolysis and sustained activation of downstream signaling pathways, including the RAF-MEK-ERK (mitogen-activated protein kinase, MAPK), PI3K-AKT-mTOR, and RalGEF-Ral cascades (3-5).

KRAS mutations occur predominantly at codons 12, 13, 61, and 146, with codon 12 accounting for more than 80% of cases (6). Among these, the KRAS G12D mutation, in which glycine at position 12 is replaced by aspartic acid, is located in the phosphate-binding loop of the GTP-binding domain and disrupts GTP hydrolysis to drive oncogenic signaling (7). In gastrointestinal (GI) malignancies, KRAS G12D constitutes the most prevalent KRAS mutation subtype in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), and it is also frequently identified in ampullary and biliary tract cancers (BTCs) (8). Although the overall frequency of KRAS mutations in gastric cancer (GC) is relatively low, G12D has been reported as the predominant subtype (9). KRAS G12D often emerges at early stages of tumorigenesis and is closely linked to aggressive biological behavior and therapeutic resistance, underscoring its clinical importance.

For decades, KRAS was regarded as a challenging therapeutic target due to several obstacles, including its picomolar affinity for GTP/GDP, the lack of deep binding pockets on its surface, the dynamic conformational changes of Switch I and II, and its membrane localization driven by posttranslational modifications (10). Moreover, early attempts to inhibit farnesylation were unsuccessful, as KRAS can alternatively undergo modification by geranylgeranyltransferase (11).

A major breakthrough was achieved in 2013, when Shokat and colleagues identified an inducible binding pocket in the Switch II region of KRAS G12C in its GDP-bound state and designed covalent small-molecule inhibitors that specifically targeted the mutant cysteine (12). This strategy led to the development of sotorasib (AMG 510) and adagrasib (MRTX849), which were approved in 2021 and 2022, respectively, for the treatment of KRAS G12C mutant non-small cell lung cancer, providing the first clinical evidence that KRAS can be directly targeted (13,14). In 2022, Wang and colleagues, employing a structure-guided optimization approach, systematically improved the contribution of each moiety to binding affinity and maximized occupancy of the Switch II pocket (15). This effort culminated in the discovery of MRTX1133, a potent and selective noncovalent KRAS G12D inhibitor with picomolar binding affinity, nanomolar cellular potency, and pronounced in vivo antitumor efficacy in KRAS G12D mutant models.

While MRTX1133 represents a major advance in directly targeting KRAS G12D, multiple biological and translational challenges remain. Accordingly, this review examines current evidence from an integrated perspective, highlighting therapeutic opportunities suggested by epidemiology and preclinical efficacy, the key resistance mechanisms and clinical barriers that constrain durable responses, and emerging strategies to address these challenges. These considerations offer a clearer perspective on where KRAS G12D inhibition currently stands and what will be required to translate this approach into meaningful clinical benefit for GI malignancies.

Therapeutic opportunities for KRAS G12D inhibition in GI cancers

Epidemiological and molecular landscape of KRAS G12D in GI malignancies

KRAS mutations constitute one of the most common oncogenic events in GI malignancies, although their overall incidence and subtype distribution vary considerably across tumor types (Table 1, Figure 1). Defining the epidemiological and molecular distribution of KRAS G12D across GI malignancies provides a theoretical foundation for identifying therapeutic opportunities for MRTX1133 and for rational patient selection in future clinical trials.

Figure 1 KRAS G12D mutation frequencies in gastrointestinal cancers. Distribution of KRAS mutations across gastrointestinal malignancies. Bars indicate the frequencies of KRAS G12D mutation and other KRAS mutations among cases. CRC, colorectal cancer; eCCA, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; GC, gastric cancer; iCCA, intrahepatic cholangiocarcinoma; PDAC, pancreatic ductal adenocarcinoma.

PDAC

PDAC is the prototypical KRAS-driven tumor, with KRAS mutations detected in more than 90% of cases, the vast majority occurring at codon 12. Within this group, G12D is the most frequent subtype, accounting for approximately 40–45%, followed by G12V (30–35%) and G12R (15–20%) (16,17). KRAS mutations arise at the earliest stages of PDAC development and are essential for both tumor initiation and maintenance. Clinically, KRAS mutations are associated with significantly poorer survival compared with KRAS wild-type disease, with the G12D subtype in particular linked to shorter survival and an increased propensity for metastasis (18).

From a population perspective, pancreatic cancer constitutes a rapidly growing global health burden, with over 500,000 new cases and more than 460,000 deaths worldwide each year, and incidence expected to rise further in the coming decades. The disease predominantly affects older individuals, with incidence increasing sharply after the age of 60, and shows marked geographic variation, with the highest age-standardized incidence rates observed in high-income regions, including North America, Western Europe, and high-income Asia-Pacific (19).

Collectively, the rising global incidence of PDAC, its pronounced age dependence, and its near-universal reliance on KRAS, predominantly the G12D subtype with adverse prognostic implications, underscore the central clinical relevance of PDAC for the development of KRAS G12D targeted therapeutic strategies.

CRC

According to recent global estimates, CRC accounts for approximately 1.9 million new cases and over 900,000 deaths annually, ranking among the leading causes of cancer-related mortality. Incidence is highest in high-Human Development Index regions and continues to rise in parts of Eastern Europe and East Asia, reflecting ongoing demographic and lifestyle changes. Both incidence and mortality increase substantially after 40 years of age, with advanced or metastatic disease predominantly diagnosed in patients older than 60 years (20). At the molecular level, KRAS mutations are detected in approximately 35–45% of cases, with codon 12 representing the major hotspot and accounting for about 65% of all mutations. In this context, G12D (~40%) and G12V (~35%) are the most common subtypes (9,21).

The clinical implications of KRAS mutations in CRC are highly context dependent and vary across disease stages. In patients with stage II/III CRC, KRAS mutations have been associated with adverse outcomes in specific molecular settings, supporting their role in prognostic stratification following curative resection (22). In metastatic CRC (mCRC), KRAS mutant tumors define a distinct biological and therapeutic subgroup characterized by intrinsic resistance to targeted therapies. Large cohort analyses consistently indicate that codon 12 mutations, including G12D, are linked to poorer clinical outcomes, reduced responsiveness to standard chemotherapy, and primary resistance to anti epidermal growth factor receptor (EGFR) antibodies such as cetuximab and panitumumab (23).

Given its high prevalence and clinical relevance, the development of selective inhibitors targeting KRAS G12D represents an important therapeutic opportunity in CRC, particularly in combination with EGFR blockade.

Biliary tract and ampullary cancers

BTCs are anatomically classified into intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBC), and represent a relatively uncommon group of GI malignancies but are associated with a disproportionately high mortality-to-incidence ratio. The highest incidence rates are observed in East Asia, particularly in China, Japan, and South Korea, as well as in parts of Southeast Asia (24).

Among these, eCCA exhibits the highest frequency of KRAS mutations, occurring in approximately 30–40% of cases; iCCA shows a lower prevalence of around 15–25%; and GBC has the lowest, at 3–8% (25-27). Across all KRAS mutations, G12D is the most common subtype, accounting for roughly 30–40% (21,28). Ampullary adenocarcinoma represents a rare GI malignancy, yet is characterized by a high frequency of KRAS mutations (approximately 45%), with G12D accounting for more than half of these alterations (29). Given the aggressive clinical behavior of BTCs, the limited availability of effective systemic therapies, and the enrichment of KRAS G12D in selected biliary and ampullary tumor subtypes, patients with recurrent or advanced disease may constitute a rational target population for selective KRAS G12D inhibitors such as MRTX1133.

GC

GC accounts for approximately 1 million new cases and 650,000 deaths each year, with a substantial proportion of cases concentrated in East Asian populations, while a growing disease burden is also being reported across several developing regions worldwide (24,30). Although KRAS mutations are detected in only about 10% of GCs, the absolute number of affected patients remains clinically meaningful because of the large global patient population. G12D is the most prevalent KRAS subtype in GC (21,31). Previous studies have shown that KRAS activation can drive the malignant transformation of gastric epithelial cells and promote the acquisition of invasive phenotypes (32,33). A comparative genomic analysis of GCs from the United States and Japan showed largely similar mutational landscapes, including comparable frequencies of KRAS alterations after adjustment for clinical factors, supporting the biological consistency of KRAS mutant GC across geographic regions (34). The development of MRTX1133 offers a novel therapeutic strategy for molecularly defined subgroups of GC and may provide clinical benefit when combined with chemotherapy or other treatment modalities.

Taken together, these findings indicate that KRAS G12D represents the predominant mutation subtype across several GI malignancies, being most prominent in PDAC and CRC and occurring at appreciable frequencies in biliary tract and GCs. This epidemiological profile provides a strong rationale for the clinical development of MRTX1133 and underscores its potential to deliver broad therapeutic benefits across multiple GI tumors.

Preclinical evidence supporting KRAS G12D targeting

Preclinical studies have provided critical proof-of-concept evidence supporting the direct pharmacological targeting of KRAS G12D. These studies collectively demonstrate the on-target activity, antitumor efficacy, and biological consequences of KRAS G12D inhibition across multiple GI cancer models.

PDAC

The emergence of MRTX1133 has, for the first time, enabled direct pharmacological inhibition of KRAS G12D, the central oncogenic driver in PDAC, and has therefore attracted substantial interest in the field.

In vitro experiments indicated that MRTX1133 selectively binds to the Switch II pocket of KRAS G12D, blocking its interaction with downstream effector proteins and broadly suppressing canonical signaling pathways at the molecular level (Figure 2A) (35). For instance, the MAPK cascade is strongly inhibited, with reduced ERK phosphorylation, leading to cell cycle arrest and decreased proliferative capacity (36). The PI3K-AKT-mTOR pathway is likewise downregulated, as evidenced by reduced AKT phosphorylation, thereby impairing cell survival signaling (37). Moreover, some studies suggest that MRTX1133 also interferes with the RalGEF-Ral pathway, thereby weakening tumor cell migration and invasion (Figure 2B) (36,38). These findings indicate that MRTX1133 can effectively disrupt the core signaling networks that PDAC cells rely on for survival, proliferation, and invasion. Beyond pathway inhibition, MRTX1133 also regulates multiple forms of programmed cell death. Treatment of pancreatic cancer cells activates caspase-3 and induces PARP cleavage, thereby triggering apoptosis (39). Metabolomic analyses have shown that MRTX1133 reduces glutathione levels and GPX4 activity, leading to lipid peroxide accumulation and thereby increasing susceptibility to ferroptosis (40). At the same time, KRAS G12D mutant PDAC cells rely on autophagy to maintain metabolic homeostasis, and MRTX1133 treatment has been shown to induce compensatory autophagic responses (41). Thus, MRTX1133 exerts multifaceted control over PDAC cell survival by regulating diverse cell death programs. Metabolic reprogramming has drawn increasing attention in pancreatic cancer research and also represents an important mechanism of MRTX1133 action. PDAC cells harboring KRAS G12D mutations exhibit strong dependence on metabolic remodeling, including the pentose phosphate pathway, glycolysis, and fatty acid metabolism. MRTX1133 inhibits flux through the pentose phosphate pathway, reducing NADPH and nucleotide synthesis, while also suppressing fatty acid synthesis and oxidation, thereby limiting energy supply. Drug treatment additionally decreases glycolysis, as reflected by reduced lactate production (42,43).

Figure 2 Mechanistic overview of MRTX1133 and its effects in PDAC and CRC. (A) MRTX1133 binds to the Switch II pocket of KRAS G12D and locks KRAS in an inactive GDP-bound state, thereby preventing its interaction with downstream effectors. (B) Based on preclinical studies in PDAC and CRC, the mechanisms of action of MRTX1133 can be categorized into four directions: direct inhibition of downstream signaling pathways; suppression of tumor metabolic reprogramming; induction of programmed cell death; and remodeling of the tumor immune microenvironment. CRC, colorectal cancer; PDAC, pancreatic ductal adenocarcinoma.

The antitumor activity of MRTX1133 has been validated in multiple in vivo models, including xenograft models, patient-derived xenograft (PDX) models, and genetically engineered mouse models. In xenograft models, MRTX1133 monotherapy significantly suppressed tumor growth, with some tumors even shrinking or completely regressing (36). In PDX models, treatment reduced the proliferation marker Ki-67 and increased apoptosis, demonstrating sustained tumor control (37). These findings strongly support the translational potential of MRTX1133. Recent studies further revealed that MRTX1133 can remodel the tumor immune microenvironment to enhance antitumor immunity, specifically by promoting CD8⁺ T cell infiltration and strengthening their Fas-dependent cytotoxicity (44,45). Despite these significant preclinical effects, incomplete tumor eradication is frequently observed following MRTX1133 monotherapy, with residual viable cells persisting in some models and predisposing to disease recurrence (46). This limitation highlights the need to better understand adaptive resistance mechanisms, which will be addressed in subsequent sections.

Overall, preclinical studies in PDAC provide compelling initial validation that direct KRAS G12D inhibition by MRTX1133 can suppress oncogenic signaling, perturb metabolic dependencies, induce multiple forms of programmed cell death, and achieve significant antitumor activity across diverse experimental models.

CRC

In CRC, KRAS-driven tumor initiation and progression is primarily mediated through the MAPK and PI3K pathways, while KRAS mutations can also cooperate with Wnt/β-catenin signaling to accelerate the acquisition of cancer stem cell-like traits and promote the selective expansion of highly metastatic clones (47). In addition, the interaction of KRAS with the TGF-β pathway enhances epithelial-mesenchymal transition (EMT), further increasing tumor cell migration and drug resistance (48). At the metabolic level, KRAS mutations reprogram CRC metabolism by enhancing glycolysis, glutamine utilization, and lipid synthesis/oxidation to support biosynthesis and redox balance (49,50). Regarding programmed cell death, sustained KRAS signaling suppresses mitochondrial apoptosis while simultaneously enhancing autophagy to support cell survival (51,52), and further confers resistance to ferroptosis through activation of the NRF2-FSP1 axis (53,54). These mechanisms provide a molecular basis for the poor prognosis of KRAS mutant mCRC and explain its inherent resistance to conventional chemotherapy and targeted therapies, while also underscoring the clinical importance of directly inhibiting KRAS and its downstream signaling in improving outcomes for patients with mCRC.

In various CRC models, MRTX1133 has validated measurable antitumor potential. In vitro, it induced cell cycle arrest, reduced Ki-67 expression, and activated caspase-3-mediated apoptosis (55). In xenograft and PDX models, MRTX1133 monotherapy suppressed tumor growth with measurable shrinkage (56). Mechanistically, similar to its action in PDAC, it binds noncovalently to KRAS G12D and blocks downstream signaling. However, CRC shows distinct biology. The efficacy of MRTX1133 is strongly influenced by EGFR signaling. Inhibition of KRAS G12D triggers rapid EGFR-mediated feedback, reactivating ERK via wild-type NRAS and HRAS, thereby limiting the durability of monotherapy (56). Consequently, combining MRTX1133 with anti-EGFR antibodies such as cetuximab or panitumumab achieves more complete ERK suppression and improved antitumor effects in CRC.

These preclinical research on MRTX1133 in CRC not only confirms its potent inhibition of KRAS G12D but also reveals CRC-specific molecular features: amplification of its inhibitory effect through KRAS degradation on the one hand, and limitations imposed by EGFR-RAS feedback and multiple resistance mechanisms on the other. These findings suggest that the optimal use of MRTX1133 in CRC will depend heavily on rational combination strategies, while its potential clinical benefit in mCRC lays the groundwork for future translational and clinical investigations.

Potential application of KRAS G12D inhibition in other GI malignancies: biliary tract, ampullary, and GCs

Although MRTX1133 has shown encouraging efficacy in preclinical studies, peer-reviewed and publicly available evidence in GI malignancies remains confined to PDAC and CRC. For BTC, ampullary adenocarcinoma, and GC, dedicated in vitro, in vivo, or clinical studies have not yet been clearly reported. Accordingly, the rationale for KRAS G12D inhibition in these malignancies remains largely at the stage of biological inference. Based on epidemiologic and molecular profiling data, KRAS G12D inhibitors appear to have strong biological plausibility in BTC and ampullary adenocarcinoma. These tumors frequently display a strong dependence on upstream receptor tyrosine kinases (RTK), with recurrent amplification or hyperactivation of EGFR, human epidermal growth factor receptor 2 (HER2), or fibroblast growth factor receptor 2 (FGFR2) observed in specific BTC subtypes (57,58). Such dependence renders the downstream RAS-MAPK cascade a central driver node. From a histogenetic perspective, both BTC and ampullary adenocarcinoma share embryologic and morphological overlap with pancreatic or biliary epithelium, suggesting a common KRAS-driven mechanism (27,59). Direct KRAS inhibition could therefore provide a strategy for downstream pathway blockade, circumventing compensatory activation from upstream feedback or parallel signaling routes. While direct evidence for MRTX1133 in these tumors is lacking, KRAS G12C inhibitors have established early proof of concept in BTC. In the KRYSTAL-1 trial (NCT03785249), the KRAS G12C inhibitor adagrasib demonstrated antitumor activity across multiple refractory solid tumors, achieving an objective response rate of approximately 41.7% in the BTC subgroup (28,60). Similarly, in the CodeBreaK 100 study, sotorasib included a small number of BTC cases, where disease stabilization was observed (61). These data support the translational potential of direct KRAS targeting in BTC.

Clinical cohort studies have shown that KRAS mutations are often associated with microsatellite-stable GC, where they correlate with advanced disease stage and reduced 5-year survival (62). This suggests that KRAS mutant GC represents a subgroup with limited benefit from immunotherapy but a potential need for targeted KRAS inhibition to improve prognosis (63). Animal models further demonstrate that sequential KRAS activation, combined with loss of tumor suppressors such as TP53, CDH1, or SMAD4, can drive the full spectrum of gastric carcinogenesis from metaplasia and dysplasia to invasive and metastatic disease (64). In early gastric neoplasia, KRAS activation cooperates with STAT3 signaling and the ARTN-GFRA3 axis to promote stem-like features, dysplastic growth, and EMT-associated invasion. These observations suggest that, beyond canonical signaling, KRAS contributes to an invasive and treatment-resistant phenotype in GC through integration with stemness- and EMT-related programs (65,66). Despite their relatively low frequency, given the substantial absolute number of GC cases worldwide, KRAS mutations in defined molecular subgroups may still represent clinically relevant targets, with KRAS G12D inhibitors potentially offering therapeutic or adjunctive benefit for selected patients within rational combination strategies.

At present, the evidence base for KRAS G12D inhibition remains concentrated in PDAC and CRC. For BTC and ampullary adenocarcinoma, pathway dependence and early proof from G12C inhibitors support both biological and translational rationale. For GC, the utility of KRAS G12D inhibitors is more likely to emerge in selected molecular subgroups or within combination regimens.

Resistance mechanisms and response strategies to KRAS G12D inhibition

Resistance mechanisms to KRAS G12D inhibition

Small-molecule targeted inhibitors in clinical practice often face the challenge of drug resistance, which constitutes the major bottleneck limiting durable efficacy. Whether targeting EGFR, ALK, or BRAF, clinical experience has clearly demonstrated that nearly all patients eventually develop acquired resistance after an initial response (67-69). KRAS inhibitors are no exception, and the problem is even more pronounced due to the “central node” position of KRAS within signaling networks, where its downstream pathways are extensive and bypass mechanisms highly diverse (70). Therefore, elucidating the resistance mechanisms of KRAS inhibitors is crucial for understanding their therapeutic limitations and for guiding rational combination strategies to maximize clinical benefit.

At the signaling level, inhibition of KRAS by MRTX1133 is inevitably accompanied by feedback activation of upstream RTKs, particularly the EGFR/ERBB family. Studies have shown that in colorectal and pancreatic cancer models, EGFR signaling can reactivate the ERK pathway via wild-type NRAS and HRAS, thereby undermining the durability of MRTX1133 monotherapy (Figure 3A) (38,55). This observation indicates that feedback through the EGFR-RAS axis is a core mechanism of acquired resistance to MRTX1133. In addition, compensatory activation of the PI3K/AKT/mTOR pathway can attenuate the drug’s antitumor activity, while upregulation of the YAP/TAZ pathway further enhances cell survival and metastatic potential (71,72). At the metabolic level, MRTX1133 treatment triggers multiple adaptive responses. First, KRAS inhibition increases oxidative stress, leading tumor cells to upregulate autophagy to replenish amino acids and glutathione, thereby buffering oxidative pressure and maintaining energy balance. Blocking autophagy significantly augments MRTX1133-induced apoptosis, underscoring its role as a critical resistance barrier (Figure 3B) (41). Second, MRTX1133 exposure markedly enhances AGER-dependent macropinocytosis in pancreatic cancer cells, enabling uptake of extracellular nutrients to sustain proliferation and survival (73). Third, ferroptosis regulation also contributes to resistance. KRAS mutant cells commonly exhibit upregulation of SLC7A11 and GPX4 with concomitant downregulation of ACSL4, which raises the ferroptosis threshold and allows tumor cells to evade lipid peroxidation-induced lethality under drug pressure (40,74). These results jointly indicate that these metabolic adaptations establish the energy and biosynthetic foundation of MRTX1133 resistance. Beyond intrinsic adaptations, the tumor microenvironment plays a critical role. Within the stromal microenvironment, cancer associated fibroblasts (CAFs) secrete NRG1, which activates ERBB2/ERBB3 signaling and enables bypass of KRAS inhibition. This paracrine-mediated resistance may be alleviated by targeting CAF-derived signaling (Figure 3C) (75). At the genetic level, resistance reflects a more fundamental challenge. Saturation mutagenesis screening has revealed that secondary mutations in the Switch II pocket of KRAS G12D (e.g., at residues H95 and Y96) can reduce binding affinity for MRTX1133, thereby conferring primary or acquired resistance (Figure 3D) (76-78). Such mutations directly disrupt the drug-target interaction and represent a critical risk that must be carefully monitored in future clinical application. Functional imaging studies have further validated the dynamics of MRTX1133 resistance. Early during treatment, tumors exhibit decreased perfusion and increased necrosis, but over time, tumor volume stabilizes or regrows, correlating with restoration of ERK phosphorylation and reactivation of KRAS signaling at the molecular level (79). This suggests that resistance can be detected not only through molecular assays but also via imaging biomarkers, offering potential for early clinical monitoring.

Figure 3 Resistance mechanisms to MRTX1133 in KRAS G12D tumors. The resistance mechanisms of MRTX1133 are multi-layered and complex, and can be summarized into four major categories. (A) Feedback activation: reactivation of the EGFR-RAS axis and compensatory activation of PI3K/AKT and YAP/TAZ signaling pathways. (B) Metabolic adaptation: ferroptosis resistance and macropinocytosis, providing alternative sources of nutrients and redox balance. (C) Microenvironmental support: CAF derived cytokines contribute to sustaining resistant tumor cell growth. (D) Genetic alterations: secondary KRAS mutations disrupt drug binding at the KRAS G12D Switch II pocket, leading to acquired resistance.

Taken together, these findings reveal that the resistance mechanisms of MRTX1133 are multi-layered and complex, involving feedback activation of the EGFR-RAS axis, compensatory PI3K/AKT and YAP/TAZ signaling, metabolic adaptations such as autophagy, macropinocytosis, and ferroptosis resistance, microenvironmental support from CAFs, and drug-binding escape due to secondary KRAS mutations. In concert, these mechanisms demonstrate that durable responses with MRTX1133 monotherapy are unlikely. Clarification of these resistance pathways underscores the substantial challenges associated with the clinical application of MRTX1133 and highlights the need to address multiple layers of adaptive escape to achieve durable therapeutic benefit.

Response strategies: rational combination therapies with MRTX1133

In response to the diverse resistance mechanisms identified in preclinical models of KRAS G12D inhibition, multiple rational combination strategies have been explored to enhance the antitumor efficacy of MRTX1133 and overcome adaptive escape pathways. One major strategy involves blocking upstream and parallel feedback signaling pathways. Since MRTX1133 treatment induces feedback activation of EGFR/HER signaling, combining MRTX1133 with anti-EGFR monoclonal antibodies (cetuximab or panitumumab) or with pan-ERBB inhibitors (such as afatinib or neratinib) has achieved marked tumor control in vitro, in organoid models, and in xenografts, and has even resensitized resistant models (37,80). As the MAPK pathway is the central effector of KRAS, avutometinib, a dual MEK/RAF inhibitor, provides more complete pathway suppression. When combined with MRTX1133 in PDAC, it achieves stronger and more durable pERK inhibition with pronounced apoptosis (81). Because the PI3K-AKT-mTOR pathway is compensatorily activated after MRTX1133 monotherapy to sustain survival signaling, co-administration of PI3K or SHP2 inhibitors achieves synergistic dual suppression of pERK and pAKT, thereby enhancing therapeutic efficacy (71). A second strategy focuses on disrupting membrane-proximal signaling and metabolic buffering that support tumor survival under KRAS inhibition. Farnesyltransferase inhibitors (FTIs), which were initially developed to block KRAS membrane localization, proved ineffective in tumors due to compensatory geranylgeranylation. However, a recent study revealed that combining FTIs with MRTX1133 synergistically suppresses tumor growth in KRAS G12D mutant PDAC models, including resistant PANC1 cells, by inhibiting HRAS and RHEB farnesylation. This results in further reduction of ERK and mTOR-S6 signaling and disruption of cell-cycle progression (82). This strategy may mitigate compensatory membrane-proximal signaling triggered by MRTX1133, thereby postponing acquired resistance. In KRAS G12D PDAC, MRTX1133 combined with the ATP synthase inhibitor bedaquiline disrupts the CMG helicase complex and enhances tumor cell death. However, resistance via an NFκB2-DDIT axis can emerge, which is overcome by adding the NFκB2 inhibitor SN52, supporting a promising triple-combination approach (83). Another complementary approach aims to lower the threshold for programmed cell death. A combinatorial drug screen targeting apoptotic pathways demonstrated that lowering the threshold for cell death effectively counters non-cell-cycle resistance. In multicellular tumor spheroid systems, MDM2 inhibitor alrizomadlin, BCL-2/BCL-xL inhibitor pelcitoclax, and IAP antagonist dasminapant each produced distinct synergistic effects with MRTX1133. Specifically, MDM2 inhibition enhanced stress-induced apoptosis and cell cycle arrest in p53-wild-type backgrounds; BCL-2/BCL-xL inhibition amplified apoptotic responses; and IAP antagonism promoted necroptotic and inflammatory cell death pathways (39,84). Finally, KRAS G12D inhibition can enhance responsiveness to conventional chemotherapy. MRTX1133 has exhibited significant synergy with multiple chemotherapeutic agents. In CRC and PDAC models, its combination with 5-fluorouracil (5-FU) deepened MAPK pathway inhibition, augmented DNA damage responses, and induced stronger cytotoxicity (85). PDAC-derived extracellular vesicles deliver KRAS G12D protein to CAFs, thereby inducing gemcitabine resistance. In preclinical models, inhibition of KRAS G12D with MRTX1133 restored chemosensitivity, and its co-administration with gemcitabine or nab-paclitaxel produced superior tumor suppression and prolonged survival (86,87). Mechanistically, KRAS inhibition weakens cellular signaling and metabolic buffering capacity, making chemotherapy-induced damage less reparable and thus enabling a dual assault on tumor cells (70). This concept is further illustrated by immunotherapeutic combinations. While MRTX1133 combined with anti-PD-1 monotherapy failed to improve survival and even promoted immunosuppression, rational regimens incorporating CXCR1/2 blockade together with anti-LAG3 and agonistic anti-41BB antibodies reprogrammed the tumor microenvironment and achieved durable complete responses in PDAC models (88).

From a translational perspective, these preclinical combination strategies highlight both the therapeutic potential and the complexity of advancing MRTX1133 into clinical practice (Table 2). The necessity for mechanism-guided combinations underscores challenges related to patient selection, treatment sequencing, toxicity management, and biomarker-driven stratification. Moreover, the reliance on multi-agent regimens raises practical considerations regarding tolerability, dosing optimization, and trial design. Together, these factors indicate that successful clinical translation of MRTX1133 will require not only effective combinations but also carefully designed strategies to balance efficacy with feasibility in clinical application.

Strengths and limitations

This review has systematically summarized the preclinical evidence regarding MRTX1133 in GI malignancies, with particular emphasis on its mechanisms of action, resistance pathways, and strategies for rational combination therapy. These studies demonstrate that direct targeting of KRAS G12D, once considered “undruggable”, can exert potent antitumor activity and open new therapeutic avenues for RAS-driven cancers.

Unique challenges for clinical translation

Despite compelling preclinical efficacy, the clinical translation of MRTX1133 faces several distinct challenges that stem largely from adaptive resistance. Extensive preclinical studies demonstrate that KRAS G12D inhibition rapidly triggers multilayered escape mechanisms, including feedback reactivation of RTK-MAPK signaling, activation of parallel survival pathways, metabolic buffering, and microenvironmental support, collectively limiting the durability of monotherapy. Beyond these common resistance patterns, emerging clinical observations reveal additional complexities. A recent case report describing a rare duodenal metastasis from KRAS G12D mutant CRC underscored the biological heterogeneity and unpredictable metastatic behavior of this molecular subtype, while also suggesting a potential role for MRTX1133 in highly selected and atypical clinical scenarios (89). Furthermore, pharmacological challenges remain. At present, MRTX1133 is primarily administered via injection and exhibits limited oral bioavailability. A prodrug formulation (Prodrug 9) has been reported to markedly improve oral exposure, indicating a possible route toward oral administration (90). However, formulation optimization, toxicity control, and dosing feasibility remain unresolved. Taken together, these issues indicate that, in addition to rational combination strategies, future clinical development of MRTX1133 will need to address drug delivery, safety management, and patient selection to enable sustainable clinical benefit.

Current clinical development gaps and comparative landscape of KRAS inhibitors

MRTX1133 has advanced to first-in-human phase I/II trials (NCT05737706), representing the first clinical attempt to directly inhibit KRAS G12D. The forthcoming clinical results will be crucial to define its therapeutic efficacy, safety profile, and resistance patterns in KRAS G12D driven tumors. In parallel, the clinical feasibility of direct KRAS targeting has been firmly established by the success of KRAS G12C inhibitors. This strategy led to the development of sotorasib (AMG 510) and adagrasib (MRTX849), which were approved in 2021 and 2022, respectively, for the treatment of KRAS G12C mutant non-small cell lung cancer, providing the first definitive clinical evidence that KRAS can be directly targeted. Although the G12C mutation is not a predominant subtype in GI malignancies such as PDAC and CRC, these agents offer an important clinical reference supporting the translational potential of allele-specific KRAS inhibition, including MRTX1133.

Beyond MRTX1133, multiple efforts are underway to expand and refine therapeutic strategies targeting KRAS G12D. ADT-1004 has been reported as a first-in-class, orally available pan-RAS inhibitor with robust antitumor activity in preclinical models of PDAC, representing an alternative modality that emphasizes broader RAS pathway suppression (91). Meanwhile, structure-based drug design approaches continue to generate novel pan-KRAS inhibitor scaffolds, illustrating active exploration of chemical space beyond the original MRTX1133 framework (92). Medicinal chemistry optimization inspired by MRTX1133 has also yielded new KRAS G12D focused compounds, such as multisubstituted pyrido[4,3-d] pyrimidine analogues incorporating deuterated linkers, which demonstrate improved pharmacological properties and further validate KRAS G12D as a tractable target (93). In addition, non-canonical strategies that indirectly address RAS-driven dependencies, exemplified by CDCP1-targeting antibody-drug conjugates showing superior efficacy in RAS-mutant pancreatic cancer models, points to complementary avenues that may be integrated with direct KRAS inhibition (94).

Overall, the expanding preclinical evidence base for MRTX1133 and other investigational KRAS-directed agents provides a strong mechanistic rationale for clinical translation. As clinical outcomes from NCT05737706 and related programs become available, these data will enable rapid refinement of patient selection, resistance monitoring, and rational combination strategies, thereby accelerating the path toward effective clinical application of KRAS G12D inhibition.

Conclusions

KRAS G12D inhibition is now demonstrably feasible, redefining the long-standing notion of KRAS as an undruggable target and establishing a new therapeutic paradigm for RAS driven cancers. Accumulating preclinical studies with MRTX1133 and related agents provide a strong mechanistic foundation for targeting this mutation across multiple GI malignancies. However, these data also reveal that adaptive resistance driven by signaling rewiring, metabolic compensation, and microenvironmental support limits the durability of KRAS G12D directed monotherapy, indicating that therapeutic efficacy is highly context dependent. Future clinical translation will therefore require biomarker-guided patient stratification, mechanism-based combination strategies, early resistance monitoring, and optimization of drug delivery and tolerability. Addressing these priorities will be essential to advance KRAS G12D inhibitors such as MRTX1133 toward meaningful clinical application.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-124/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-124/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Wang X, Wu J, Xiao A, et al. Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs. Mol Cancer 2025;24:229. [Crossref] [PubMed]
2. Mondal K, Posa MK, Shenoy RP, et al. KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways. Cells 2024;13:1221. [Crossref] [PubMed]
3. Bulle A, Liu P, Seehra K, et al. Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer. Nat Commun 2024;15:2503. [Crossref] [PubMed]
4. McDaid WJ, Wilson L, Adderley H, et al. The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRAS(G12D)-driven non-small cell lung cancer. Mol Cancer 2024;23:253. [Crossref] [PubMed]
5. Yang Q, Lang C, Wu Z, et al. MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway. J Exp Clin Cancer Res 2019;38:391. [Crossref] [PubMed]
6. Cook JH, Melloni GEM, Gulhan DC, et al. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun 2021;12:1808. [Crossref] [PubMed]
7. Li Y, Yang L, Li X, et al. Inhibition of GTPase KRAS(G12D): a review of patent literature. Expert Opin Ther Pat 2024;34:701-21. [Crossref] [PubMed]
8. Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev 2020;39:1029-38. [Crossref] [PubMed]
9. Zhu G, Pei L, Xia H, et al. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer 2021;20:143. [Crossref] [PubMed]
10. Zhu C, Guan X, Zhang X, et al. Targeting KRAS mutant cancers: from druggable therapy to drug resistance. Mol Cancer 2022;21:159. [Crossref] [PubMed]
11. Karasic TB, Chiorean EG, Sebti SM, et al. A Phase I Study of GGTI-2418 (Geranylgeranyl Transferase I Inhibitor) in Patients with Advanced Solid Tumors. Target Oncol 2019;14:613-8. [Crossref] [PubMed]
12. Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548-51. [Crossref] [PubMed]
13. Nakajima EC, Drezner N, Li X, et al. FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. Clin Cancer Res 2022;28:1482-6. [Crossref] [PubMed]
14. Dhillon S. Adagrasib: First Approval. Drugs 2023;83:275-85. [Crossref] [PubMed]
15. Wang X, Allen S, Blake JF, et al. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor. J Med Chem 2022;65:3123-33. [Crossref] [PubMed]
16. Zhang J, Darman L, Hassan MS, et al. Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope Oncol Rep 2023;50:206. (Review). [Crossref] [PubMed]
17. Luo J. KRAS mutation in pancreatic cancer. Semin Oncol 2021;48:10-8. [Crossref] [PubMed]
18. Dai M, Jahanzaib R, Liao Y, et al. Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection. Front Oncol 2022;12:1074538. [Crossref] [PubMed]
19. Leiphrakpam PD, Chowdhury S, Zhang M, et al. Trends in the Global Incidence of Pancreatic Cancer and a Brief Review of its Histologic and Molecular Subtypes. J Gastrointest Cancer 2025;56:71. [Crossref] [PubMed]
20. Wu S, Zhang Y, Lin Z, et al. Global burden of colorectal cancer in 2022 and projections to 2050: incidence and mortality estimates from GLOBOCAN. BMC Cancer 2025;25:1770. [Crossref] [PubMed]
21. Wang L, Saeedi BJ, Mahdi Z, et al. Analysis of KRAS Mutations in Gastrointestinal Tract Adenocarcinomas Reveals Site-Specific Mutational Signatures. Mod Pathol 2023;36:100014. [Crossref] [PubMed]
22. Kang D, Li J, Li Y, et al. Prognostic significance of KRAS, NRAS, BRAF, and PIK3CA mutations in stage II/III colorectal cancer: A retrospective study and meta-analysis. PLoS One 2025;20:e0320783. [Crossref] [PubMed]
23. Moretto R, Rossini D, Murgioni S, et al. KRASG12D-Mutated Metastatic Colorectal Cancer: Clinical, Molecular, Immunologic, and Prognostic Features of a New Emerging Targeted Alteration. JCO Precis Oncol 2024;8:e2400329. [Crossref] [PubMed]
24. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
25. Thongyoo P, Chindaprasirt J, Aphivatanasiri C, et al. KRAS Mutations in Cholangiocarcinoma: Prevalence, Prognostic Value, and KRAS G12/G13 Detection in Cell-Free DNA. Cancer Genomics Proteomics 2025;22:112-26. [Crossref] [PubMed]
26. Montal R, Sia D, Montironi C, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol 2020;73:315-27. [Crossref] [PubMed]
27. Iida K, Matsui Y, Urabe Y, et al. Association of KRAS variants with survival and therapeutic outcomes in biliary tract cancers. ESMO Open 2025;10:105306. [Crossref] [PubMed]
28. Moffat GT, Hu ZI, Meric-Bernstam F, et al. KRAS Allelic Variants in Biliary Tract Cancers. JAMA Netw Open 2024;7:e249840. [Crossref] [PubMed]
29. Zeissig MN, Ashwood LM, Kondrashova O, et al. Next batter up! Targeting cancers with KRAS-G12D mutations. Trends Cancer 2023;9:955-67. [Crossref] [PubMed]
30. Jiang N. Global burden and future trends of gastric cancer in women of reproductive age: estimates from the GBD 2021 Study, 1990-2050. Front Oncol 2025;15:1616936. [Crossref] [PubMed]
31. Huber A, Allam AH, Dijkstra C, et al. Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines. Cell Rep 2024;43:114616. [Crossref] [PubMed]
32. Min J, Vega PN, Engevik AC, et al. Heterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach. Nat Commun 2019;10:5549. [Crossref] [PubMed]
33. Hu F, Zhang S, Chai J. METTL3 Promotes Gastric Cancer Progression via Modulation of FNTA-Mediated KRAS/ERK Signaling Activation. Mol Cancer Res 2025;23:724-38. [Crossref] [PubMed]
34. Nakauchi M, Court C, Walch HS, et al. Genomic and clinical parallels between US and Japanese gastric cancers: a propensity score-matched cohort study. Br J Surg 2025;112:znaf280. [Crossref] [PubMed]
35. Kim HN, Gasmi-Seabrook GMC, Uchida A, et al. Switch II Pocket Inhibitor Allosterically Freezes KRAS(G12D) Nucleotide-binding Site and Arrests the GTPase Cycle. J Mol Biol 2025;437:169162. [Crossref] [PubMed]
36. Kemp SB, Cheng N, Markosyan N, et al. Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Cancer Discov 2023;13:298-311. [Crossref] [PubMed]
37. Hallin J, Bowcut V, Calinisan A, et al. Anti-tumor efficacy of a potent and selective non-covalent KRAS(G12D) inhibitor. Nat Med 2022;28:2171-82. [Crossref] [PubMed]
38. Gulay KCM, Zhang X, Pantazopoulou V, et al. Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma. Cancer Res 2023;83:3001-12. [Crossref] [PubMed]
39. Becker JH, Metropulos AE, Spaulding C, et al. Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer. Cancer Res 2024;84:3629-39. [Crossref] [PubMed]
40. Xu C, Lin W, Zhang Q, et al. MGST1 facilitates novel KRAS(G12D) inhibitor resistance in KRAS(G12D)-mutated pancreatic ductal adenocarcinoma by inhibiting ferroptosis. Mol Med 2024;30:199. [Crossref] [PubMed]
41. Han L, Meng L, Liu J, et al. Macroautophagy/autophagy promotes resistance to KRAS(G12D)-targeted therapy through glutathione synthesis. Cancer Lett 2024;604:217258. [Crossref] [PubMed]
42. Jiang X, Wang T, Zhao B, et al. KRAS(G12D)-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC. Cell Rep Med 2025;6:101966. [Crossref] [PubMed]
43. Orsburn BC. Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRAS(G12D) Inhibitor MRTX1133. J Proteome Res 2023;22:3703-13. [Crossref] [PubMed]
44. Mahadevan KK, McAndrews KM, LeBleu VS, et al. KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells. Cancer Cell 2023;41:1606-1620.e8. [Crossref] [PubMed]
45. Kumarasamy V, Wang J, Frangou C, et al. The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer. Cancer Res 2024;84:1115-32. [Crossref] [PubMed]
46. Wei D, Wang L, Zuo X, et al. A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer. Clin Cancer Res 2024;30:655-62. [Crossref] [PubMed]
47. Lemieux E, Cagnol S, Beaudry K, et al. Oncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer. Oncogene 2015;34:4914-27. [Crossref] [PubMed]
48. Flum M, Dicks S, Teng YH, et al. Canonical TGFβ signaling induces collective invasion in colorectal carcinogenesis through a Snail1- and Zeb1-independent partial EMT. Oncogene 2022;41:1492-506. [Crossref] [PubMed]
49. Zhang C, Yu R, Li S, et al. KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression. Cell Death Differ 2025;32:2225-38. [Crossref] [PubMed]
50. Zhang J, Zou S, Fang L. Metabolic reprogramming in colorectal cancer: regulatory networks and therapy. Cell Biosci 2023;13:25. [Crossref] [PubMed]
51. Khawaja H, Briggs R, Latimer CH, et al. Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer. Mol Cancer Ther 2023;22:135-49. [Crossref] [PubMed]
52. Taraborrelli L, Şenbabaoğlu Y, Wang L, et al. Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer. Nat Commun 2023;14:5945. [Crossref] [PubMed]
53. Müller F, Lim JKM, Bebber CM, et al. Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ 2023;30:442-56. [Crossref] [PubMed]
54. Yang L, Zhang Y, Zhang Y, et al. Mechanism and application of ferroptosis in colorectal cancer. Biomed Pharmacother 2023;158:114102. [Crossref] [PubMed]
55. Feng J, Hu Z, Xia X, et al. Feedback activation of EGFR/wild-type RAS signaling axis limits KRAS(G12D) inhibitor efficacy in KRAS(G12D)-mutated colorectal cancer. Oncogene 2023;42:1620-33. [Crossref] [PubMed]
56. Kataoka M, Kitazawa M, Nakamura S, et al. Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRAS(G12D) Inhibitor, in Colorectal Cancer Treatment. Anticancer Res 2023;43:4341-8. [Crossref] [PubMed]
57. Inoue K, Nakamura Y, Caughey B, et al. Clinicomolecular Profile and Efficacy of Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Therapy for HER2-Amplified Advanced Biliary Tract Cancer. JCO Precis Oncol 2025;9:e2400718. [Crossref] [PubMed]
58. Angerilli V, Fornaro L, Pepe F, et al. FGFR2 testing in cholangiocarcinoma: translating molecular studies into clinical practice. Pathologica 2023;115:71-82. [Crossref] [PubMed]
59. Tsagkalidis V, Langan RC, Ecker BL. Ampullary Adenocarcinoma: A Review of the Mutational Landscape and Implications for Treatment. Cancers (Basel) 2023;15:5772. [Crossref] [PubMed]
60. Bekaii-Saab TS, Yaeger R, Spira AI, et al. Adagrasib in Advanced Solid Tumors Harboring a KRAS(G12C) Mutation. J Clin Oncol 2023;41:4097-106. [Crossref] [PubMed]
61. Kabbara KW, Cannon T, Winer A, et al. Molecular Pathogenesis of Cholangiocarcinoma: Implications for Disease Classification and Therapy. Oncology (Williston Park) 2022;36:492-8. [Crossref] [PubMed]
62. Polom K, Das K, Marrelli D, et al. KRAS Mutation in Gastric Cancer and Prognostication Associated with Microsatellite Instability Status. Pathol Oncol Res 2019;25:333-40. [Crossref] [PubMed]
63. Shitara K, Janjigian YY, Ajani J, et al. Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial. Nat Med 2025;31:1519-30. [Crossref] [PubMed]
64. Lu Z, Zhong A, Liu H, et al. Dissecting the genetic and microenvironmental factors of gastric tumorigenesis in mice. Cell Rep 2022;41:111482. [Crossref] [PubMed]
65. Wang XL, Jin GX, Dong XQ. ARTN-GFRA3 axis induces epithelial-mesenchymal transition phenotypes, migration, and invasion of gastric cancer cells via KRAS signaling. Neoplasma 2024;71:266-78. [Crossref] [PubMed]
66. Kim H, Jang B, Zhang C, et al. Targeting Stem Cells and Dysplastic Features With Dual MEK/ERK and STAT3 Suppression in Gastric Carcinogenesis. Gastroenterology 2024;166:117-31. [Crossref] [PubMed]
67. Du Z, Kan H, Sun J, et al. Molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist Updat 2025;82:101266. [Crossref] [PubMed]
68. Poei D, Ali S, Ye S, et al. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. Cancer Drug Resist 2024;7:20. [Crossref] [PubMed]
69. Imani S, Roozitalab G, Emadi M, et al. The evolution of BRAF-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies. Front Oncol 2024;14:1504142. [Crossref] [PubMed]
70. Dilly J, Hoffman MT, Abbassi L, et al. Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer. Cancer Discov 2024;14:2135-61. [Crossref] [PubMed]
71. Hao MW, Zhang TX, Dong D, et al. Enhancing KRAS G12D inhibitor sensitivity in pancreatic cancer through SHP2/PI3K pathway. Med Oncol 2025;42:139. [Crossref] [PubMed]
72. Yang W, Zhang M, Zhang TX, et al. YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis. JCI Insight 2024;9:e178535. [Crossref] [PubMed]
73. Li C, Liu Y, Liu C, et al. AGER-dependent macropinocytosis drives resistance to KRAS-G12D-targeted therapy in advanced pancreatic cancer. Sci Transl Med 2025;17:eadp4986. [Crossref] [PubMed]
74. Zou J, Shi X, Wu Z, et al. MRTX1133 attenuates KRAS(G12D) mutated-colorectal cancer progression through activating ferroptosis activity via METTL14/LINC02159/FOXC2 axis. Transl Oncol 2025;52:102235. [Crossref] [PubMed]
75. Han J, Xu J, Liu Y, et al. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Genes Dev 2023;37:818-28. [Crossref] [PubMed]
76. Keats MA, Han JJW, Lee YH, et al. A Nonconserved Histidine Residue on KRAS Drives Paralog Selectivity of the KRASG12D Inhibitor MRTX1133. Cancer Res 2023;83:2816-23. [Crossref] [PubMed]
77. Lokhandwala J, Smalley TB, Tran TH. Structural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance. Front Oncol 2024;14:1394702. [Crossref] [PubMed]
78. Choi J, Shin JY, Kim TK, et al. Site-specific mutagenesis screening in KRAS(G12D) mutant library to uncover resistance mechanisms to KRAS(G12D) inhibitors. Cancer Lett 2024;591:216904. [Crossref] [PubMed]
79. Gupta M, Choi H, Kemp SB, et al. Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy. Clin Cancer Res 2025;31:2663-74. [Crossref] [PubMed]
80. Kilroy-Gehret MK, Wischmeier C, Park S, et al. Co-targeting KRASG12D and the HER family is efficacious in colorectal cancer. Carcinogenesis 2025;46:bgaf036. [Crossref] [PubMed]
81. Toyokuni E, Horinaka M, Nishimoto E, et al. Combination Therapy of Avutometinib and MRTX1133 Synergistically Suppresses Cell Growth by Inducing Apoptosis in KRASG12D-Mutated Pancreatic Cancer. Mol Cancer Ther 2025;24:1537-45. [Crossref] [PubMed]
82. Molnár E, Baranyi M, Szigeti K, et al. Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer. Pathol Oncol Res 2024;30:1611948. [Crossref] [PubMed]
83. Xiao J, Kim J, Park B, et al. Targeting DNA helicase CMG complex and NFκB2-driven drug-resistant transcriptional axis to effectively treat KRAS(G12D)-mutated pancreatic cancer. Exp Hematol Oncol 2025;14:79. [Crossref] [PubMed]
84. Coussens NP, Dexheimer TS, Silvers T, et al. Combinatorial screen with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell type tumor spheroids. SLAS Discov 2025;33:100230. [Crossref] [PubMed]
85. Tajiknia V, Pinho-Schwermann M, Srinivasan PR, et al. Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation. Am J Cancer Res 2024;14:4523-36. [Crossref] [PubMed]
86. Singhal A, Styers HC, Rub J, et al. A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. Cancer Discov 2024;14:2122-34. [Crossref] [PubMed]
87. Liu X, Yang J, Huang S, et al. Pancreatic cancer-derived extracellular vesicles enhance chemoresistance by delivering KRAS(G12D) protein to cancer-associated fibroblasts. Mol Ther 2025;33:1134-53. [Crossref] [PubMed]
88. Liu Y, Han J, Hsu WH, et al. Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model. Cancer Discov 2025;15:162-78. [Crossref] [PubMed]
89. Ismail A, Boateng WKB, Alnakeb A, et al. Rare Case of Duodenal Metastasis From Colon Cancer: Review of Literature and Insights on Novel Therapies. Case Rep Gastrointest Med 2025;2025:8864636. [Crossref] [PubMed]
90. Ji X, Li Y, Kong X, et al. Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation. ACS Omega 2023;8:7211-21. [Crossref] [PubMed]
91. Bandi DSR, Nagaraju GP, Sarvesh S, et al. ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma. Mol Cancer 2025;24:76. [Crossref] [PubMed]
92. Aladinskiy V, Mantsyzov AB, Kruse C, et al. Identification of Novel pan-KRAS Inhibitors via Structure-Based Drug Design, Scaffold Hopping, and Biological Evaluation. ACS Med Chem Lett 2025;16:1282-9. [Crossref] [PubMed]
93. Xiao X, Feng J, Ma J, et al. Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3-d]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRASG12D Inhibitors. J Med Chem 2023;66:15524-49.
94. Um YJ, Noh HD, Cho JG, et al. CDCP1-targeting ADC outperforms standard therapies in Ras-mutant pancreatic cancer. Mol Ther Oncol 2025;33:201024. [Crossref] [PubMed]