Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer

摘要: EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to inhibitors gefitinib erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but not shown be sufficient render mutant/amplified cancers resistant inhibitors. We created a model for studying by prolonged exposure of gefitinib-sensitive carcinoma cell line (H3255; amplified) vitro. The resulting T790M mutation small fraction the alleles that was undetected direct sequencing identified only highly HPLC-based technique. In cancer cells mutations amplifications, exogenous introduction effectively conferred continued ErbB-3/PI3K/Akt signaling when cis an activating mutation. Moreover, activation PI3K PIK3CA oncogenic mutant, p110α E545K, abrogate gefitinib-induced apoptosis. These findings suggest allelic dilution biologically significant may go oncogenes restoration via either or other mechanisms can provide gefitinib.