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 de Sousa e Melo, Chris Bolen, Anneleen Daemen, Alan P. Venook, Federico Innocenti, Heinz Josef Lenz, Carlos Bais

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number5478
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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