MRTX1133

KRAS inhibitors, including KRAS G12D inhibitor MRTX1133, are promising therapeutics against KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), but drug resistance limits their efficacy. Our study reveals that robust induction of apoptosis using a combination of BCL-xL PROTAC degrader and an mTOR inhibitor, significantly enhances MRTX1133 efficacy in PDAC models without increasing toxicity to normal tissues.

In murine models of MRTX1133-resistant PDAC, BET inhibition cooperated with MRTX1133 to markedly extend overall survival. As BET inhibitors are currently under clinical testing, the combination of MRTX1133 and BET inhibitors warrants further investigation, particularly in tumors that have developed resistance to KRAS inhibition.

RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.

KRAS mutations and hyperglycaemia drive O-GlcNAcylation of CLDN18.2 at its C-terminal T204 site. O-GlcNAcylated CLDN18.2 promotes poor prognosis and reduces the effectiveness of CLDN18.2-targeted therapies. Low dose MRTX1133 restores CLDN18.2 membrane localisation by reducing its O-GlcNAcylation and augments CLDN18.2-targeted therapy efficacy, offering a novel combinatorial strategy for KRAS-mutant PDAC.

While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849)...To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways...Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.

Allele-specific inhibitors are likely to find their place in combinations that suppress adaptive bypass (e.g. SOS1/SHP2, MEK/ERK, EGFR) while leveraging immunotherapy or metabolic vulnerabilities. Prospective biomarker integration and resistance-informed trial designs will be decisive in translating early signals into durable patient benefit.

MRTX1133 induced alterations associated with mesenchymal-to-epithelial transition; furthermore, lower levels of activated Erk, altered FAK expression, and activation were observed. In addition to the antiproliferative effects of MRTX1133, our in vitro and in vivo results indicate the importance of MRTX1133 as a potential antimetastatic drug in PDAC therapy.

When combined with the KRAS G12D inhibitor MRTX1133, MDP5 resensitized resistant cancer cells. This combination synergistically enhanced apoptosis and proliferation inhibition, outperforming the standard-of-care, Gemcitabine (GEM)...Mechanistically, dual inhibition suppresses AKT/YAP signaling, depletes CD44+/ALDH+ cells, and shifts the tumor immune milieu (↑CD8a, ↑CD86, ↓Ly-6G). By integrating molecular targeting with multi-pathway blockade, this work addresses two major barriers-resistance and delivery-and outlines a generalizable strategy to improve precision nano therapy for KRAS-mutant pancreatic cancer.

We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations...Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress growth of KRAS-G12D-mutant PDAC cells...Single-cell RNA sequencing suggested that Palbociclib treatment induces tumor vascularization, perhaps contributing to the lack of drug synergy observed in vivo. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of placing combination therapies into a suitable context.

Compound 53a exhibited comparable binding to KRAS-G12D (ΔTm = 12.1 °C) and potent in vitro activities (IC50 values of 8.4 nM and 19.5 nM against p-ERK and proliferation of AsPC-1 cells, respectively), compared to those of MRTX1133 as a reference standard...In vivo study showed that 53a significantly inhibited tumor growth in the AsPC-1 xenograft mouse model by inhibiting KRAS-G12D. These findings support 53a as a promising lead candidate for the development of selective KRAS-G12D targeted cancer therapies.

Robust antitumor activity of AOH1996 in combination with RMC-6236 was observed in PDAC tumoroids. In vivo , the combination of AOH1996 with sotorasib or MRTX1133 reduced tumor growth rates compared to single-agent therapy, with no impact on mouse body weight. Residual tumor analysis showed sustained pERK and Myc inhibition in the combination arm. In conclusion, combination of AOH1996 with KRAS inhibitors is a promising therapeutic strategy for KRAS-driven PDAC, warranting further clinical investigation.

Significant progress has been made in the development of small-molecule inhibitors: non-covalent inhibitors (e.g., MRTX1133) exploit ionic interactions (salt bridges) with the mutant aspartic acid residue to achieve high affinity and selectivity; novel covalent strategies are emerging, including strain-release alkylation and tri-complex inhibitors (e.g., RMC-9805). The article further evaluates the status of candidate drugs currently in clinical trials and addresses the critical challenges of acquired resistance, which may arise through secondary mutations or bypass signaling pathways. Finally, it emphasizes future directions, including the optimization of drug delivery via nanoparticles and the implementation of combination therapies to enhance efficacy and achieve durable clinical responses.