ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.

RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

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Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests N.R. is on the scientific advisory board (SAB) and owns equity in Beigene, Zai Labs, MapKure, Ribon, and Effector. N.R. is also on the SAB of Astra Zeneca and Chugai and a past SAB member of Novartis, Millennium-Takeda, Kura, and Araxes. N.R. is a consultant to RevMed, Tarveda, Array-Pfizer, Boeringher Ingelheim, and Eli Lilly. He receives research funding from Revmed, Astra Zeneca, Array Pfizer, and Boerhinger Ingelheim and owns equity in Kura Oncology and Fortress. Z.Y. is a past SAB member of MapKure and currently an employee of Loxo Oncology at Lilly. R.Y. has received research support from Array BioPharma/Pfizer, Novartis, and Boehringer Ingelheim (Ingelheim, Germany) and served as an advisor for Array BioPharma/Pfizer, Mirati Therapeutics, and Natera. O.A.W. received research funding from H3B Biomedicine and personal fees from H3B Biomedicine, Foundation Medicine Inc, Merck, and Jansen. C.M.R. has consulted regarding cancer drug development with AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and serves on the SAB of Bridge Medicines and Harpoon Therapeutics. P.A.J. has received consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Merrimack Pharmaceuticals, Chugai Pharmaceuticals, Ariad Pharmaceuticals, Eli Lilly and Company, Araxes Pharma, Ignyta, Novartis, Mirati Therapeutics, Takeda Oncology, Daiichi Sankyo, Biocartis, Voronoi, SFJ Pharmaceuticals, and Loxo Oncology; receives post-marketing royalties from DFCI-owned intellectual property on EGFR mutations licensed to Lab Corp; has sponsored research agreements with Astra Zeneca, Daichi Sankyo, Boehringer Ingelheim, PUMA, Eli Lilly, Astellas Pharmaceuticals, and Takeda Oncology; and has stock ownership in Gatekeeper Pharmaceuticals and Loxo Oncology. F.M. is shareholder in Olema, Opna, Kura, BridgeBio, Avidity, Quartz, Quadriga, and Wellspring and is a consultant for Amgen, Pfizer, Daiichi Sankyo, Ideaya, BridgeBio, PMV, Caris, and Aduro.