MRTX1133

Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This appears 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.

While KRAS was long considered undruggable, the development of mutant-specific inhibitors, including covalent inhibitors targeting KRASG12C (such as Sotorasib and Adagrasib) and non-covalent inhibitors targeting KRASG12D (such as Mirati's MRTX1133), has shown promise. In cellular models of KRAS-mutated NSCLC and PDAC, this nanoplatform achieved comparable or superior therapeutic outcomes with respect to the individual drugs. This study provides a compelling proof-of-concept for the in vitro delivery of KRASG12C mutant-specific inhibitors and degraders to human tumors through a tumor microenvironment-activated nanomedicine approach and lays the groundwork for future studies in physiologically relevant models to assess TME-specific activation and tumor selectivity.

Notably, combining a G9a degrader (G9D-4) with the KRASG12D inhibitor MRTX1133 elicited synergistic anti-tumor effects in KRASG12D-mutant tumoroids. Overall, our study provides preclinical insights from a small PDAC and BTC tumoroid cohort, supporting tumoroid-based platforms for exploratory drug screening and pharmacogenomic analyses and suggesting potential therapeutic directions that warrant further validation.

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.