title: Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling.
abstract: 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.
authors: Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
authors: Juliann
authors: J
authors: Chmielecki
authors: Jasmine
authors: J
authors: Foo
authors: Geoffrey R
authors: GR
authors: Oxnard
authors: Katherine
authors: K
authors: Hutchinson
authors: Kadoaki
authors: K
authors: Ohashi
authors: Romel
authors: R
authors: Somwar
authors: Lu
authors: L
authors: Wang
authors: Katherine R
authors: KR
authors: Amato
authors: Maria
authors: M
authors: Arcila
authors: Martin L
authors: ML
authors: Sos
authors: Nicholas D
authors: ND
authors: Socci
authors: Agnes
authors: A
authors: Viale
authors: Elisa
authors: E
authors: de Stanchina
authors: Michelle S
authors: MS
authors: Ginsberg
authors: Roman K
authors: RK
authors: Thomas
authors: Mark G
authors: MG
authors: Kris
authors: Akira
authors: A
authors: Inoue
authors: Marc
authors: M
authors: Ladanyi
authors: Vincent A
authors: VA
authors: Miller
authors: Franziska
authors: F
authors: Michor
authors: William
authors: W
authors: Pao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D019143:Evolution, Molecular; D005260:Female; D000077156:Gefitinib; D018773:Genes, erbB-1 / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008962:Models, Theoretical; D009154:Mutation; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib