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

Author

Listed:
  • 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.)

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.

Suggested Citation

  • 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 , 2022. "ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33172-5
    DOI: 10.1038/s41467-022-33172-5
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