Letter abstract
Nature Medicine 14, 1351 - 1356 (2008)
Published online: 30 November 2008 | doi:10.1038/nm.1890
Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers
Jeffrey A Engelman1,2,3,12, Liang Chen4,5,12, Xiaohong Tan4,5, Katherine Crosby6, Alexander R Guimaraes7,8, Rabi Upadhyay7,8, Michel Maira9, Kate McNamara4,5, Samanthi A Perera4,5, Youngchul Song1, Lucian R Chirieac10, Ramneet Kaur1,3, Angela Lightbown6, Jessica Simendinger6, Timothy Li2, Robert F Padera10, Carlos García-Echeverría9, Ralph Weissleder7,8,11, Umar Mahmood7,8, Lewis C Cantley2,3,11 & Kwok-Kin Wong3,4,5
Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-
catalytic subunit (encoded by PIK3CA)1. They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110- mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110- H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan–PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography–computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.
- Massachusetts General Hospital Cancer Center, 149 Thirteenth Street, Charlestown, Massachusetts 02129, USA.
- Beth Israel Deaconness Medical Center Cancer Center, Beth Israel Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Ludwig Center at Dana-Farber–Harvard Cancer Center, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Cell Signaling Technology, 3 Trask Lane, Danvers, Massachusetts 01923, USA.
- Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Charlestown, Massachusetts 02129, USA.
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
- Novartis Institutes for Biomedical Research, Oncology Disease Area, Klybeckstrasse 141, CH-4057 Basel, Switzerland.
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
- These authors contributed equally to this work.
Correspondence to: Lewis C Cantley2,3,11 e-mail: lewis_cantley@hms.harvard.edu
Correspondence to: Kwok-Kin Wong3,4,5 e-mail: KWONG1@PARTNERS.ORG
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