MRTX1133

Combined MRTX1133 and olaparib treatment produced synergistic cytotoxicity in vitro and durable tumor regression in vivo, even in MRTX1133-resistant models, and remodeled the tumor immune microenvironment with enhanced CD8+ T-cell infiltration. These findings demonstrate that co-targeting KRASG12D and PARP exploits an induced DNA-repair vulnerability to achieve synthetic lethality and immune activation in KRASG12D-driven PDAC.

These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies.

This in silico study predicts Carteolol as a potential dual-targeting therapeutic agent, requiring biochemical and cellular validation before clinical relevance can be established.

While KRAS was historically considered undruggable, mutant-specific inhibitors, including non-covalent KRAS G12D inhibitor MRTX1133, have emerged...Efficacy in patient-derived organoids was comparable. This study demonstrates the potential of this nanomedicine platform for targeted delivery of KRAS mutant-specific inhibitors to human tumors.

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.