Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations.
Jacqueline H StarrettAlexis A GuernetMaria Emanuela CuomoKamrine E PoelsIris K van Alderwerelt van RosenburghAmy NagelbergDylan FarnsworthKristin S PriceHina KhanKumar Dilip AshtekarMmaserame GaefeleDeborah AyeniTyler F StewartAlexandra KuhlmannSusan M KaechArun M UnniRobert J HomerWilliam W LockwoodFranziska MichorSarah B GoldbergMark A LemmonPaul D SmithDarren A E CrossKaterina PolitiPublished in: Cancer research (2020)
Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo. SIGNIFICANCE: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg.
Keyphrases
- epidermal growth factor receptor
- small cell lung cancer
- advanced non small cell lung cancer
- tyrosine kinase
- end stage renal disease
- ejection fraction
- newly diagnosed
- chronic kidney disease
- healthcare
- prognostic factors
- machine learning
- peritoneal dialysis
- single cell
- emergency department
- mouse model
- climate change
- risk assessment
- big data
- drug induced
- diabetic rats
- adverse drug