Rapamycin Prevents the Development and Progression of Mutant Epidermal Growth Factor Receptor Lung Tumors with the Acquired Resistance Mutation T790M
Shigeru Kawabata,
José R. Mercado-Matos,
M. Christine Hollander,
Danielle Donahue,
Willie Wilson III,
Lucia Regales,
Mohit Butaney,
William Pao,
Kwok-Kin Wong,
Pasi A. Jänne,
Phillip A. Dennis
Affiliations
Shigeru Kawabata
Department of Oncology, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224, USA
José R. Mercado-Matos
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
M. Christine Hollander
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Danielle Donahue
Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD 20892, USA
Willie Wilson III
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Lucia Regales
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Mohit Butaney
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
William Pao
Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Kwok-Kin Wong
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Pasi A. Jänne
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Phillip A. Dennis
Department of Oncology, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224, USA
Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.
