KRAS mutation

P2, N=150, Not yet recruiting, Verastem, Inc.

This study is the first to examine p27 localization in WT KRAS CRC. The observed association between WT KRAS expression and cytoplasmic p27 localization highlights a potential mechanism contributing to tumour progression through altered p27 function.

Competition with MRTX849 blocked KRAS degradation, supporting on-target covalent engagement at Cys12. These findings establish carborane as a compact, functional HyT that drives proteasome-dependent degradation of endogenous KRASG12C and suppresses downstream signaling, broadening degrader design to include an E3-independent modality for the degradation of oncogenic proteins.

Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.

Moreover, we observed that KRASG12C/EML4-ALK tumor cells kept under constant pressure with KRASG12C inhibitors exhibit sensitivity to single-agent ALK inhibitors, suggesting a potential for rationally designed sequential treatments. Mechanistically, EML4-ALK bypasses KRASG12C inhibition by activating wild-type RAS, highlighting an additional therapeutic opportunity for multi-selective RAS inhibitors under clinical investigation.

To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust anti-proliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo.

P2, N=105, Not yet recruiting, Verastem, Inc.

Application in CRC cellular scenarios, using only nanograms of total RNA, allowed differential profiling of basal and pathway-activated states across five cell lines, revealing distinct RNA methylation patterns associated with diverse biological and genetic backgrounds. Moreover, as proof of concept, an octuple-detection configuration was implemented for parallel analysis of the four methylations in two cell types, wild-type and harboring the clinically relevant KRAS G12V mutation, allowing the evaluation of associations between the target epimark expression levels and this oncogenic point mutation.

P1/2, N=58, Completed, Associacio Per A La Recerca Oncologica | Phase classification: P=N/A --> P1/2 | --> Completed

The results confirm watch-and-wait as standard of care for early-stage CLL patients, especially in high-risk CLL characterized by del(17p) and/or mutated TP53. EudraCT Number: 2013-003211-22.

RA acts as a novel KRASG12C inhibitor that directly targets the mutant cysteine-12 residue, suppressing NSCLC progression through inhibition of the KRAS/AKT/ERK pathway and enhancement of anti-tumor immune activity. These findings highlight RA's therapeutic potential for KRASG12C-driven NSCLC and offer new insights for the development of targeted cancer therapies.