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: Juliann Chmielecki, Jasmine Foo, Geoffrey R Oxnard, Katherine Hutchinson, Kadoaki Ohashi, Romel Somwar, Lu Wang, Katherine R Amato, Maria Arcila, Martin L Sos, Nicholas D Socci, Agnes Viale, Elisa de Stanchina, Michelle S Ginsberg, Roman K Thomas, Mark G Kris, Akira Inoue, Marc Ladanyi, Vincent A Miller, Franziska Michor, William Pao
• Journal: Science translational medicine (Sci Transl Med) Vol. 3 Issue 90 Pg. 90ra59 (Jul 06 2011) ISSN: 1946-6242 [Electronic] United States
• PMID: 21734175 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolines
• Erlotinib Hydrochloride
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics, metabolism)
• Erlotinib Hydrochloride
• Evolution, Molecular
• Female
• Gefitinib
• Genes, erbB-1 (drug effects)
• Humans
• Mice
• Mice, Nude
• Models, Theoretical
• Mutation
• Neoplasm Transplantation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinazolines (pharmacology, therapeutic use)