ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer
Radia Marie 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 de Sousa e Melo, Chris Bolen, Anneleen Daemen, Alan P. Venook, Federico Innocenti, Heinz‐Josef Lenz, Carlos Bais
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.