RAS mutation

P3, N=900, Recruiting, Revolution Medicines, Inc.

P1/2, N=162, Recruiting, Association Gercor | Not yet recruiting --> Recruiting

Patients with metastatic colorectal cancer (mCRC) who have progressed on fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic agents, and anti-epidermal growth factor receptor (EGFR) therapies have limited treatment options and poor prognosis, with a median overall survival (mOS) of ∼6 months on single-agent regorafenib or trifluridine/tipiracil. Tumor assessments occur every 8 weeks; follow-up continues for up to 18 months after enrolment. Optional translational research includes tumor, blood, and stool sampling to explore biomarkers of response and resistance.

We dissect the mechanistic underpinnings and clinical performance of foundational regimens such as FOLFOX, FOLFIRI, and CAPOX, and analyze how key driver alterations, including RAS/RAF mutations, HER2 amplification, MSI/MMR status, and VEGF-mediated angiogenesis, influence disease progression and therapeutic selection...Emerging advances such as KRAS G12C inhibitors, multi-kinase angiogenesis modulators, antibody-drug conjugates, ribosome biogenesis inhibitors, AI-guided therapeutic algorithms, and ctDNA-based monitoring are also discussed. By integrating mechanistic insights with clinical evidence, this review offers a structured framework to better understand current treatment paradigms and future directions in biomarker-driven precision therapy for colon cancer.

These molecular tools have the potential to change how CRC is managed by earlier detection and more precise predictive biomarkers. However, large-scale validation and clinical standardization are still crucial for their extensive utilization.

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.

A novel EGFR mSig that captures the transcriptional footprint of EGFR activation revealed a subset of EGFR WT LUADs with "mt-like" features. mSig refines LUAD taxonomy beyond mutation-only pie-chart models by incorporating lineage and co-mutation context. Lineage-directed stratification with co-alteration identifies clinically relevant groups across EGFR and RAS states and highlights new treatment opportunities for patients currently considered "oncogene-negative.".

For 30 paired tissue-plasma samples, the overall concordance was 93.33% with a positive concordance of 86.67%. These findings highlight SPE as a cost-effective, rapid, and highly sensitive approach for clinical RAS genotyping in CRC and for guiding targeted therapy.

These changes were accompanied by altered muscle mitochondria morphology, with no concomitant changes in neuronal ultrastructure or neuronal mitochondria. Overall, this suggests that neurofibromin mutations affect multiple signaling cascades downstream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.

The overall survival rates were comparable between the RAS mutation emergence and persistent RAS wild-type groups (p = 0.88). In RAS wild-type mCRC, female patients and patients with high CEA levels may benefit from precision treatment strategies that incorporate real-time genetic monitoring.

Our real-world experience with L/P in metastatic BRAFWT-ATC demonstrates the clinical efficacy and safety of this combination, consistent with prior reports. A prospective clinical trial in the United States is ongoing (NCT#04171622).

Despite these advances, challenges persist, including therapeutic resistance, tumor heterogeneity, limited immunotherapy efficacy in microsatellite-stable disease, and rising early-onset CRC. Future progress relies on precision medicine, ctDNA-guided monitoring, microbiome-targeted strategies, and optimized surgical selection.