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

Lick Pui Lai, Nicole Fer, William Burgan, Vanessa E Wall, Bingfang Xu, Daniel Soppet, Dominic Esposito, Dwight V Nissley, Frank McCormick

Proceedings of the National Academy of Sciences of the United States of America 2022 Feb 01

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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.

Citation

Lick Pui Lai, Nicole Fer, William Burgan, Vanessa E Wall, Bingfang Xu, Daniel Soppet, Dominic Esposito, Dwight V Nissley, Frank McCormick. Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 2022 Feb 01;119(5)