KRAS mutation

We critically discuss the apparently conflicting evidence on STK33's essentiality in KRAS-driven cancers, and argue for refined targeting strategies of STK33 (including degradation rather than simply kinase inhibition) alongside biomarker-guided patient stratification. With continued optimization of pharmacokinetics, selectivity, and mechanism of action, STK33 remains a promising, albeit challenging, target in precision oncology.

Colonoscope-derived mucus is a promising localized cfDNA source for detecting early colorectal neoplasia. This approach may serve as a colonoscopy-integrated adjunct within existing screening pathways and may support post-procedure risk stratification and surveillance optimization.

This refinement operates at the cellular level without displacing the tissue-level Correa sequence documented in long-term human cohorts. It nominates the remodelled stem-cell niche as a tractable pharmacological target and warrants molecular profiling of at-risk progenitor populations to complement, rather than replace, histopathological surveillance.

Immunohistochemical analyses of pancreatic cancer tissues revealed high VEGFR2 expression in 83% (67/80) of samples, significantly exceeding the levels observed in normal pancreatic tissues. These results underscore VEGFR2 as a promising molecular target and propose a novel therapeutic avenue for KRAS-mutant cancers.

In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFNγ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC.

P2, N=90, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2026 --> Sep 2026

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.