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

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 KRAS^G12C-dependent lung cancer cell lines, when KRAS is inhibited by ARS1620, a KRAS^G12C 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.

SUBMITTER: Lai LP 

PROVIDER: S-EPMC8812530 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature