Cell Reports (Feb 2022)
CRAF dimerization with ARAF regulates KRAS-driven tumor growth
- Avinashnarayan Venkatanarayan,
- Jason Liang,
- Ivana Yen,
- Frances Shanahan,
- Benjamin Haley,
- Lilian Phu,
- Erik Verschueren,
- Trent B. Hinkle,
- David Kan,
- Ehud Segal,
- Jason E. Long,
- Tony Lima,
- Nicholas P.D. Liau,
- Jawahar Sudhamsu,
- Jason Li,
- Christiaan Klijn,
- Robert Piskol,
- Melissa R. Junttila,
- Andrey S. Shaw,
- Mark Merchant,
- Matthew T. Chang,
- Donald S. Kirkpatrick,
- Shiva Malek
Affiliations
- Avinashnarayan Venkatanarayan
- Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Jason Liang
- Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Ivana Yen
- Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Frances Shanahan
- Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Benjamin Haley
- Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Lilian Phu
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Erik Verschueren
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Trent B. Hinkle
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- David Kan
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Ehud Segal
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Jason E. Long
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Tony Lima
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Nicholas P.D. Liau
- Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Jawahar Sudhamsu
- Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Jason Li
- Department of Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Christiaan Klijn
- Department of Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Robert Piskol
- Department of Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Melissa R. Junttila
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Andrey S. Shaw
- Department of Research Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Mark Merchant
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Matthew T. Chang
- Department of Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Donald S. Kirkpatrick
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Shiva Malek
- Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Corresponding author
- Journal volume & issue
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Vol. 38,
no. 6
p. 110351
Abstract
Summary: KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit.
