ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer

Radia M. Johnson (), Xueping Qu (), Chu-Fang Lin, Ling-Yuh Huw, Avinashnarayan Venkatanarayan, Ethan Sokol, Fang-Shu Ou, Nnamdi Ihuegbu, Oliver A. Zill, Omar Kabbarah, Lisa Wang, Richard Bourgon, Felipe Sousa e Melo, Chris Bolen, Anneleen Daemen, Alan P. Venook, Federico Innocenti, Heinz-Josef Lenz and Carlos Bais ()
Additional contact information
Radia M. Johnson: Genentech, Inc.
Xueping Qu: Genentech, Inc.
Chu-Fang Lin: Genentech, Inc.
Ling-Yuh Huw: Genentech, Inc.
Avinashnarayan Venkatanarayan: Genentech, Inc.
Ethan Sokol: Foundation Medicine, Inc.
Fang-Shu Ou: Mayo Clinic
Nnamdi Ihuegbu: Guardant Health, Inc
Oliver A. Zill: Genentech, Inc.
Omar Kabbarah: Genentech, Inc.
Lisa Wang: Genentech, Inc.
Richard Bourgon: Genentech, Inc.
Felipe Sousa e Melo: Genentech, Inc.
Chris Bolen: Genentech, Inc.
Anneleen Daemen: Genentech, Inc.
Alan P. Venook: University of California, San Francisco
Federico Innocenti: University of North Carolina at Chapel Hill
Heinz-Josef Lenz: USC Norris Comprehensive Cancer Center
Carlos Bais: Genentech, Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.

Date: 2022
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DOI: 10.1038/s41467-022-33172-5

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