Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling.

Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, Wang L, Amato KR, Arcila M, Sos ML, Socci ND, Viale A, de Stanchina E, Ginsberg MS, Thomas RK, Kris MG, Inoue A, Ladanyi M, Miller VA, Michor F, Pao W
Sci Transl Med. 2011 3 (90): 90ra59

PMID: 21734175 · PMCID: PMC3500629 · DOI:10.1126/scitranslmed.3002356

Non-small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.

MeSH Terms (19)

Animals Antineoplastic Agents Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Drug Resistance, Neoplasm ErbB Receptors Erlotinib Hydrochloride Evolution, Molecular Female Gefitinib Genes, erbB-1 Humans Mice Mice, Nude Models, Theoretical Mutation Neoplasm Transplantation Protein Kinase Inhibitors Quinazolines

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