ArticleCancer discovery2025
Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
Article in Cancer discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Daraxonrasib and the era of pan-RAS inhibition: mechanisms, clinical advances, and resistance landscapes.Experimental hematology & oncology · 2026Review
- HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.Science signaling · 2026Article
- Article
- RAS Inhibitor RMC-7977 Blocks Vascular Overgrowth of NRASJournal of cellular and molecular medicine · 2026Article
- Allele-specific KRAS signaling: shaping tumor immunity and therapeutic response in lung adenocarcinoma.Signal transduction and targeted therapy · 2026Article
- DARS2 serves as an independent prognostic factor and participates in multiple biological processes in bladder urothelial carcinoma.Translational andrology and urology · 2026Article
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- CRISPR-Cas9 Screening Identifies Resistance Mechanisms to KRAS Inhibition in Pancreatic Cancer.Cancer research · 2026Article
- Article
- Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- From PIK3CA Mutations to Rational PI3K Inhibition for the Treatment of Colorectal Cancer.Molecular diagnosis & therapy · 2026Review
- Adamantinoma-like Ewing sarcoma with NRAS Q61R mutation-a hitherto unreported mutation in a case from the nasal cavity.Virchows Archiv : an international journal of pathology · 2025Article
- Pancreatic Cells Are Resistant to KRASQ61L Expression due to Hyperactive ERK/MAPK Signaling and Apoptosis Induction.Cancer research communications · 2025Article
- KRAS G12C Inhibition in Solid Tumors: Biological Breakthroughs, Clinical Evidence, and Open Challenges.Cancers · 2025Review
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Authors and funding
24 authors.
Funding
Abstract
RAS genes are frequently mutated in cancer, often at codons 12 and 61. With the recent introduction of RAS inhibitors, we can now directly investigate the effects of specific RAS mutations in cancer cells. In this study, we demonstrate that in tumors with RASG12X mutations, mutant RAS can be activated by receptor tyrosine kinases (RTK), and PI3K activation is dependent on mutant RAS. Conversely, RASQ61X mutations activate the MAPK cascade independently of RTKs, and inhibition of RASQ61X impairs MAPK pathway activation but leaves the PI3K pathway unaffected. Our characterization of these distinct features of G12X and Q61X mutations suggests that co-inhibition of RAS and RTKs selectively inhibits the growth of RASG12X-mutant tumors, both in vitro and in vivo, regardless of the RAS isoform and tumor type. Additionally, our findings offer a mechanistic explanation for the increased frequency of RASQ61X mutations as a secondary resistance mechanism against EGFR inhibition in colorectal cancer. SIGNIFICANCE: RAS inhibition in multiple tumor types reveals the difference between G12 mutants and Q61 mutants in their cooperation with upstream regulators and downstream effectors to promote oncogenic signaling. Our findings provide the rationale for combinatorial approaches and contribute to explaining the nonuniform distribution of RAS mutations, de novo and at resistance.
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