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Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors
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Journal Article
Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors
2022
Overview
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.
Publisher
National Academy of Sciences
Subject
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cell Proliferation - drug effects
/ Extracellular signal-regulated kinase
/ Intracellular Signaling Peptides and Proteins - drug effects
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Kinases
/ MAP Kinase Signaling System - physiology
/ Mice
/ Mouse Embryonic Stem Cells - metabolism
/ Protein Kinase Inhibitors - pharmacology
/ Proteins
/ Proto-Oncogene Proteins B-raf - metabolism
/ Proto-Oncogene Proteins c-raf - metabolism
/ raf Kinases - antagonists & inhibitors
