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

Juliann Chmielecki, Jasmine Foo, Geoffrey R. Oxnard, Katherine Hutchinson, Kadoaki Oohashi, 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 MichorWilliam Pao

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number90ra59
JournalScience Translational Medicine
Volume3
Issue number90
DOIs
Publication statusPublished - Jul 6 2011
Externally publishedYes

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Neoplasms
Pharmaceutical Preparations
erbB-1 Genes
Mutation
Growth
Appointments and Schedules
Theoretical Models
Pharmacokinetics
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. / Chmielecki, Juliann; Foo, Jasmine; Oxnard, Geoffrey R.; Hutchinson, Katherine; Oohashi, Kadoaki; Somwar, Romel; Wang, Lu; Amato, Katherine R.; Arcila, Maria; Sos, Martin L.; Socci, Nicholas D.; Viale, Agnes; De Stanchina, Elisa; Ginsberg, Michelle S.; Thomas, Roman K.; Kris, Mark G.; Inoue, Akira; Ladanyi, Marc; Miller, Vincent A.; Michor, Franziska; Pao, William.

In: Science Translational Medicine, Vol. 3, No. 90, 90ra59, 06.07.2011.

Research output: Contribution to journalArticle

Chmielecki, J, Foo, J, Oxnard, GR, Hutchinson, K, Oohashi, 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 2011, 'Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling', Science Translational Medicine, vol. 3, no. 90, 90ra59. https://doi.org/10.1126/scitranslmed.3002356
Chmielecki, Juliann ; Foo, Jasmine ; Oxnard, Geoffrey R. ; Hutchinson, Katherine ; Oohashi, Kadoaki ; Somwar, Romel ; Wang, Lu ; Amato, Katherine R. ; Arcila, Maria ; Sos, Martin L. ; Socci, Nicholas D. ; Viale, Agnes ; De Stanchina, Elisa ; Ginsberg, Michelle S. ; Thomas, Roman K. ; Kris, Mark G. ; Inoue, Akira ; Ladanyi, Marc ; Miller, Vincent A. ; Michor, Franziska ; Pao, William. / Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. In: Science Translational Medicine. 2011 ; Vol. 3, No. 90.
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