Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations

Iris K. Alderwerelt van Rosenburgh, David M. Lu, Michael J. Grant, Steven E. Stayrook, Manali Phadke, Zenta Walther, Sarah B. Goldberg, Katerina Politi, Mark A. Lemmon (), Kumar D. Ashtekar () and Yuko Tsutsui ()
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Iris K. Alderwerelt van Rosenburgh: Yale University School of Medicine
David M. Lu: Yale University School of Medicine
Michael J. Grant: Yale University School of Medicine
Steven E. Stayrook: Yale University School of Medicine
Manali Phadke: Yale School of Public Health
Zenta Walther: Yale University School of Medicine
Sarah B. Goldberg: Yale University School of Medicine
Katerina Politi: Yale University School of Medicine
Mark A. Lemmon: Yale University School of Medicine
Kumar D. Ashtekar: Yale University School of Medicine
Yuko Tsutsui: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low KM, ATP). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

Date: 2022
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DOI: 10.1038/s41467-022-34398-z

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