MRTX1133

Further exploration revealed that, while WFS1 is regulated by the MAPK and PI3K/AKT pathways in MRTX1133-sensitive cells, acquired resistance is associated with downregulation of the E3 ubiquitin ligase Smurf1, leading to increased WFS1 protein stability. Overall, these results highlight WFS1 as an adaptive factor and potential therapeutic target in KRASG12D-driven malignancies, offering a novel approach to enhance the efficacy of KRASG12D inhibitors and overcome acquired resistance.

However, DIO promoted recruitment of gMDSC and reductions in cytotoxic T cells within the 2838c3 T-cell inflamed TME, correlating with loss of control of microscopic disease. These findings suggest that DIO reduces the potency of targeted KRASG12D inhibition in T cell-inflamed PDAC.

We systematically evaluated the biochemical, biological, and therapeutic activity of single, dual, and triple regimens combining the KRASG12D inhibitor MRTX1133 with cetuximab (EGFR inhibitor), alpelisib (PI3Kα inhibitor), or trametinib (MEK inhibitor) in a panel of patient-derived tumoroids and xenografts (PDXs) from metastatic CRC. Collectively, our results identify dual KRASG12D - EGFR inhibition as the regimen delivering maximal pathway suppression and therapeutic benefit in clinically relevant CRC models, with no clear advantage from more complex triple combinations. This work encourages prioritizing KRAS-EGFR co-targeting over multi-agent strategies that risk added toxicity, and provides a strong rationale for advancing KRASG12D inhibitors + cetuximab as a backbone targeted therapy in future clinical trials for KRASG12D-mutant CRC.

Several candidate ligands exhibited favorable binding affinity, stable proteinligand interactions, and enhanced structural stability compared with reference inhibitors, including MRTX1133 and BI-2852. Molecular dynamics analyses further supported the stability of the predicted complexes and the involvement of key binding residues within the KRAS G12D pocket. These findings demonstrate that MPFF-IS can efficiently identify potential KRAS G12D inhibitors and may provide a useful computational framework for precision drug discovery targeting difficult oncogenic proteins.

Transmembrane oncoMUCs promote immune evasion in PDA through EGFR/UNC5B signaling, and their targeting enhances the efficacy of K-rasG12D inhibition, suggesting oncoMUCs as novel immune regulators and therapeutic targets in PDA.

In this study, we identified potential natural inhibitors of KRAS G12D through structure-based virtual screening, using MRTX1133 as a reference...In vitro analysis in PANC-1 cells carrying the KRAS G12D mutation confirmed dose-dependent cytotoxicity, reactive oxygen species accumulation, and apoptosis induction, validating the anticancer potential of the compounds. These results highlight the therapeutic potential of mangiferin and hesperetin 7-O-glucoside as KRAS G12D inhibitors in PDAC and support their further exploration in preclinical models for efficacy and combinatorial strategies.

KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

Consistently, FRA2 and MTOR levels strongly correlate in PDAC patient samples. Collectively, these findings uncover a mechanistic interplay between Fra-2 and the mTOR pathway in MRTX-1133-resistant PDAC, highlighting that targeting Fra-2 may represent a valuable approach to enhance the efficacy of KRASi.

Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This seems to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms.

When combined with cytotoxic agents, including paclitaxel, SN38, gemcitabine and cisplatin, MRTX1133 reduced the sensitivity to cell cycle-dependent chemotherapeutic agents, namely paclitaxel, SN38 and gemcitabine, while not affecting the activity of the non-cell cycle-dependent agent cisplatin. The present study therefore provided preclinical evidence for the potential utility of KRAS (G12D)-targeted therapy in OMC and highlights the importance of sequential rather than concurrent scheduling of MRTX1133 with cell cycle-dependent chemotherapy to optimize therapeutic efficacy.

We evaluated KRAS G12D -specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRAS mut organoid and orthotopic PDX models of AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

These findings underscore the importance of combination therapeutic approaches in overcoming resistance. This review summarizes current evidence on the mechanisms of action, resistance pathways, and potential combination strategies of MRTX1133 in digestive system cancers, and discusses its translational relevance and clinical implications for KRAS G12D mutant malignancies.