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.

P1, N=130, Recruiting, Bayer | Not yet recruiting --> Recruiting

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.

P2, N=90, Not yet recruiting, Genfleet Therapeutics (Shanghai) Inc.

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.

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.

P1, N=130, Not yet recruiting, Bayer

P1, N=42, Recruiting, D3 Bio (Wuxi) Co., Ltd | Not yet recruiting --> Recruiting

P3, N=588, Recruiting, Incyte Corporation

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.

Through screening a 2,652-kinase inhibitor library, we discovered that Osimertinib, an EGFR tyrosine kinase inhibitor, and its analogs strongly synergize with MRTX1133 against both parental and MRTX1133-resistant cells. NT-1 strongly synergized with MRTX1133 to suppress EGFR/MAPK signaling and induce apoptosis in an MRTX1133-resistant patient-derived organoid model of CRC. We present novel small molecule combinations with the potential to overcome the limitations of KRAS inhibitors with direct clinical translational applications.

Collectively, our findings suggest that the combination of DT2216/everolimus potentiates the anti-tumor efficacy of MRTX1133 associated with enhanced apoptosis induction and inhibition of compensatory survival signaling.