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

Nat Commun. 2022 Sep 19;13(1):5478. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents, Immunological* / adverse effects
  • Antineoplastic Agents, Immunological* / pharmacology
  • Antineoplastic Agents, Immunological* / therapeutic use
  • Cetuximab* / adverse effects
  • Cetuximab* / pharmacology
  • Cetuximab* / therapeutic use
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • DNA-Binding Proteins* / genetics
  • Drug Resistance, Neoplasm* / genetics
  • Humans
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Transcription Factors* / genetics


  • ARID1A protein, human
  • Antineoplastic Agents, Immunological
  • DNA-Binding Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab