Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
Open Access
- 10 November 2022
- journal article
- research article
- Published by Springer Nature in Nature Communications
- Vol. 13 (1) , 1-16
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 lowKM, 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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P50-CA196530, T32-CA233414, P50-CA196530, P50-CA196530, P30-CA016359, R01-CA198164, P50-CA196530, R03-CA259881)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- Conquer Cancer Foundation (2021YIA-0474838505)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- Arnold and Mabel Beckman Foundation (17-001959)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
This publication has 80 references indexed in Scilit:
- Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domainBiochemical Journal, 2012
- Conformational Transitions in the Membrane Scaffold Protein of Phospholipid Bilayer NanodiscsMolecular & Cellular Proteomics, 2011
- Escherichia coli Processivity Clamp β from DNA Polymerase III Is Dynamic in SolutionBiochemistry, 2011
- Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancerBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2010
- Recognition-Domain Focused Chemosensors: Versatile and Efficient Reporters of Protein Kinase ActivityJournal of the American Chemical Society, 2008
- The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATPProceedings of the National Academy of Sciences, 2008
- Epidermal growth factor receptor mutations in lung cancerNature Reviews Cancer, 2007
- An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor ReceptorCell, 2006
- Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to GefitinibNew England Journal of Medicine, 2004
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973