Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations

Authors

Michelangelo Marasco
Dinesh Kumar
Santiago Garcia Borrego
Tessa Seale
Giulia Maddalena
Riccardo Mezzadra
Kylie Belanger
Soren Cole
Brayan Perez
Wei Luan
Radha Mukherjee
Ilinca Aricescu
Vladimir Markov
Yuxin Zhu
Sabrina Arena
Alberto Bardelli
Elisa de Stanchina
Scott W Lowe
Richard A Burkhart
Jacquelyn W Zimmerman
Rona Yaeger
Scott E Kopetz
Neal Rosen
Sandra Misale

Language

English

Publication Date

7-3-2025

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-24-0614

PMID

40294008

PMCID

PMC12226219

PubMedCentral® Posted Date

1-3-2026

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Mutation, ras Proteins, Receptor Protein-Tyrosine Kinases, Phosphatidylinositol 3-Kinases, Neoplasms, MAP Kinase Signaling System, Humans, Cell Line, Tumor, Female, Animals, Mice, Mice, Inbred C57BL, Piperazines

Published Open-Access

yes

Recommended Citation

Marasco, Michelangelo; Kumar, Dinesh; Garcia Borrego, Santiago; et al., "Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations" (2025). Faculty, Staff and Student Publications. 6017.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6017