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Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors

  1. Author:
    Lai, Lick Pui
    Fer,Nicole [ORCID]
    Burgan,William [ORCID]
    Wall,Vanessa [ORCID]
    Xu,Bingfang
    Soppet,Daniel
    Esposito,Dom [ORCID]
    Nissley,Dwight [ORCID]
    McCormick, Frank [ORCID]

  2. Author Address

    RAS initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702; licklai@ymail.com frank.mccormick@ucsf.edu., RAS initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.,
    1. Year: 2022
    2. Date: Feb 01
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 119
    2. 5
  4. Type of Article: Article
  1. Abstract:

    RAF inhibitors unexpectedly induce ERK signaling in normal and tumor cells with elevated RAS activity. Paradoxical activation is believed to be RAS dependent. In this study, we showed that LY3009120, a pan-RAF inhibitor, can unexpectedly cause paradoxical ERK activation in KRASG12C-dependent lung cancer cell lines, when KRAS is inhibited by ARS1620, a KRASG12C inhibitor. Using H/N/KRAS-less mouse embryonic fibroblasts, we discovered that classical RAS proteins are not essential for RAF inhibitor-induced paradoxical ERK signaling. In their absence, RAF inhibitors can induce ERK phosphorylation, ERK target gene transcription, and cell proliferation. We further showed that the MRAS/SHOC2 complex is required for this process. This study highlights the complexity of the allosteric RAF regulation by RAF inhibitors, and the importance of other RAS-related proteins in this process. Copyright © 2022 the Author(s). Published by PNAS.

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External Sources

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  2. DOI: 10.1073/pnas.2113491119
  3. PMID: 35091470
  4. PII : 2113491119

Library Notes

  1. Fiscal Year: FY2021-2022
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