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

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, Brianna R. Silverman, Myshal D. Morris, Ty Running Fisher, Eden Beyene, Yvonne Y. Li, Andrew D. Cherniack, Federica Piccioni, J. Kevin Hicks, Andrew S. Chi, Daniel P. Cahill, Jorg Dietrich, Tracy T. Batchelor, David E. Root, Cory M. Johannessen and Matthew Meyerson ()
Additional contact information
Tikvah K. Hayes: Dana-Farber Cancer Institute & Harvard Medical School
Elisa Aquilanti: Dana-Farber Cancer Institute & Harvard Medical School
Nicole S. Persky: The Broad Institute of M.I.T. and Harvard
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
Lindsay Westlake: The Broad Institute of M.I.T. and Harvard
Lior Golomb: Dana-Farber Cancer Institute & Harvard Medical School
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
Andrew D. Cherniack: Dana-Farber Cancer Institute & Harvard Medical School
Federica Piccioni: The Broad Institute of M.I.T. and Harvard
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
Matthew Meyerson: Dana-Farber Cancer Institute & Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45594-4

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