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

• Published in: Nature communications Vol. 13; no. 1; p. 5478
• Main Authors: Johnson, Radia M., Qu, Xueping, Lin, Chu-Fang, Huw, Ling-Yuh, Venkatanarayan, Avinashnarayan, Sokol, Ethan, Ou, Fang-Shu, Ihuegbu, Nnamdi, Zill, Oliver A., Kabbarah, Omar, Wang, Lisa, Bourgon, Richard, de Sousa e Melo, Felipe, Bolen, Chris, Daemen, Anneleen, Venook, Alan P., Innocenti, Federico, Lenz, Heinz-Josef, Bais, Carlos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/39; 45; 45/23; 45/91; 49; 631/67/395; 631/67/69; 692/4028/67/1504/1885; 692/4028/67/69; Bevacizumab; Biomarkers; Cancer; Colorectal cancer; Colorectal carcinoma; Epidermal growth factor receptors; Epigenetics; Humanities and Social Sciences; MAP kinase; Monoclonal antibodies; multidisciplinary; Mutation; Patients; Science; Science (multidisciplinary); Targeted cancer therapy; Tumors; Vascular endothelial growth factor
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33172-5

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. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated colorectal cancer tumors, however, its relationship with treatment response remains to be explored. Here, the authors suggest that ARID1A mutations may confer intrinsic and acquired resistance to cetuximab treatment.