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Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants

Author

Listed:
  • Tikvah K. Hayes

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard
    University of California)

  • Elisa Aquilanti

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

  • Nicole S. Persky

    (The Broad Institute of M.I.T. and Harvard
    The Broad Institute of M.I.T. and Harvard
    Aera Therapeutics)

  • Xiaoping Yang

    (The Broad Institute of M.I.T. and Harvard)

  • Erica E. Kim

    (Dana-Farber Cancer Institute & Harvard Medical School)

  • Lisa Brenan

    (The Broad Institute of M.I.T. and Harvard)

  • Amy B. Goodale

    (The Broad Institute of M.I.T. and Harvard)

  • Douglas Alan

    (The Broad Institute of M.I.T. and Harvard)

  • Ted Sharpe

    (The Broad Institute of M.I.T. and Harvard Cambridge)

  • Robert E. Shue

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

  • Lindsay Westlake

    (The Broad Institute of M.I.T. and Harvard)

  • Lior Golomb

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

  • Brianna R. Silverman

    (Dana-Farber Cancer Institute & Harvard Medical School)

  • Myshal D. Morris

    (Harvard Medical School)

  • Ty Running Fisher

    (Harvard Medical School)

  • Eden Beyene

    (Harvard Medical School)

  • Yvonne Y. Li

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

  • Andrew D. Cherniack

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

  • Federica Piccioni

    (The Broad Institute of M.I.T. and Harvard
    Merck Research Laboratories)

  • J. Kevin Hicks

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Andrew S. Chi

    (Massachusetts General Hospital)

  • Daniel P. Cahill

    (Massachusetts General Hospital)

  • Jorg Dietrich

    (Massachusetts General Hospital)

  • Tracy T. Batchelor

    (Brigham and Women’s Hospital & Harvard Medical School)

  • David E. Root

    (The Broad Institute of M.I.T. and Harvard)

  • Cory M. Johannessen

    (The Broad Institute of M.I.T. and Harvard
    Novartis Institutes for Biomedical Research)

  • Matthew Meyerson

    (Dana-Farber Cancer Institute & Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

Abstract

The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.

Suggested Citation

  • Tikvah K. Hayes & Elisa Aquilanti & Nicole S. Persky & Xiaoping Yang & Erica E. Kim & Lisa Brenan & Amy B. Goodale & Douglas Alan & Ted Sharpe & Robert E. Shue & Lindsay Westlake & Lior Golomb & Brian, 2024. "Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45594-4
    DOI: 10.1038/s41467-024-45594-4
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    References listed on IDEAS

    as
    1. Jacqulyne P. Robichaux & Xiuning Le & R. S. K. Vijayan & J. Kevin Hicks & Simon Heeke & Yasir Y. Elamin & Heather Y. Lin & Hibiki Udagawa & Ferdinandos Skoulidis & Hai Tran & Susan Varghese & Junqin H, 2021. "Structure-based classification predicts drug response in EGFR-mutant NSCLC," Nature, Nature, vol. 597(7878), pages 732-737, September.
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