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Figure S3 from Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations

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posted on 2025-07-03, 07:20 authored by 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
<p>Figure S3 shows the Western blot analysis of early signaling dynamics following treatment with trametinib in two HTVI-KRAS G12D and two HTVI-KRAS Q61R lines.</p>

Funding

National Institutes of Health (NIH)

Break Through Cancer (BTC)

Black Acral Melanoma Initiative

FY24 Maryland Cancer Moonshot (MCM) Research Grant

Dana & Albert R. Broccoli Charitable Foundation Grant

AIRC under BRIDGE 2022-ID 27321 project

AIRC under IG 2023 -ID 29286 project

Finanziamento dell’Unione Europea NextGeneration EU M4 C2 investimento 1.1.-P2022E3BTH

Cancer Center Core Grant P30

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    DOI - Is supplement to Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations

ARTICLE 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. 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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    Cancer Discovery

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    Keywords

    Cell SignalingGuanine nucleotide binding proteins and effectorsDrug ResistanceOncogenes & Tumor SuppressorsKras

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