Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors
| Autor: | Lick Pui Lai, Nicole Fer, William Burgan, Vanessa E. Wall, Bingfang Xu, Daniel Soppet, Dominic Esposito, Dwight V. Nissley, Frank McCormick |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAP Kinase Signaling System RAF inhibitors Antineoplastic Agents Cell Line Mice Rare Diseases Cell Line Tumor MRAS paradoxical ERK activation Animals Phosphorylation Lung Protein Kinase Inhibitors Cancer Cell Proliferation Tumor Multidisciplinary RAS-related GTPase Intracellular Signaling Peptides and Proteins Mouse Embryonic Stem Cells Fibroblasts RAS GTPase Proto-Oncogene Proteins c-raf Mutation ras Proteins raf Kinases Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 119, iss 5 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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