Direct inhibition of RAS reveals the features of oncogenic signaling driven by RAS G12 and Q61 mutations Journal Article
| Authors: | Marasco, M.; Kumar, D.; Garcia Borrego, S.; Seale, T.; Maddalena, G.; Mezzadra, R.; Belanger, K.; Cole, S.; Perez, B.; Luan, W.; Mukherjee, R.; Aricescu, I.; Markov, V.; Zhu, Y.; Arena, S.; Bardelli, A.; de Stanchina, E.; Lowe, S. W.; Burkhart, R. A.; Zimmerman, J. W.; Yaeger, R.; Kopetz, S. E.; Rosen, N.; Misale, S. |
| Article Title: | Direct inhibition of RAS reveals the features of oncogenic signaling driven by RAS G12 and Q61 mutations |
| 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. ©2025 American Association for Cancer Research. |
| Keywords: | signal transduction; genetics; mutation; mouse; animal; animals; mice; epidermal growth factor receptor; drug effect; cell line, tumor; tumor cell line; ras protein; ras proteins; erbb receptors; humans; human |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 7 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-07-01 |
| Start Page: | 1392 |
| End Page: | 1409 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-0614 |
| PUBMED: | 40294008 |
| PROVIDER: | scopus |
| PMCID: | PMC12226219 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Neal Rosen -- Source: Scopus |
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