Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

Jeffrey A. Engelman, Liang Chen, Xiaohong Tan, Katherine Crosby, Alexander Guimaraes, Rabi Upadhyay, Michel Maira, Kate McNamara, Samanthi A. Perera, Youngchul Song, Lucian R. Chirieac, Ramneet Kaur, Angela Lightbown, Jessica Simendinger, Timothy Li, Robert F. Padera, Carlos García-Echeverría, Ralph Weissleder, Umar Mahmood, Lewis C. CantleyKwok Kin Wong

Research output: Contribution to journalArticle

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Abstract

Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)1351-1356
Number of pages6
JournalNature Medicine
Volume14
Issue number12
DOIs
StatePublished - Dec 2008
Externally publishedYes

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MAP Kinase Kinase Kinase 3
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositols
Lung Neoplasms
Phosphotransferases
Sirolimus
Neoplasms
Tumors
Mutation
Positron emission tomography
Magnetic resonance
Tomography
Catalytic Domain
Microscopic examination
Magnetic Resonance Imaging
Clinical Trials
Imaging techniques
dactolisib

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. / Engelman, Jeffrey A.; Chen, Liang; Tan, Xiaohong; Crosby, Katherine; Guimaraes, Alexander; Upadhyay, Rabi; Maira, Michel; McNamara, Kate; Perera, Samanthi A.; Song, Youngchul; Chirieac, Lucian R.; Kaur, Ramneet; Lightbown, Angela; Simendinger, Jessica; Li, Timothy; Padera, Robert F.; García-Echeverría, Carlos; Weissleder, Ralph; Mahmood, Umar; Cantley, Lewis C.; Wong, Kwok Kin.

In: Nature Medicine, Vol. 14, No. 12, 12.2008, p. 1351-1356.

Research output: Contribution to journalArticle

Engelman, JA, Chen, L, Tan, X, Crosby, K, Guimaraes, A, Upadhyay, R, Maira, M, McNamara, K, Perera, SA, Song, Y, Chirieac, LR, Kaur, R, Lightbown, A, Simendinger, J, Li, T, Padera, RF, García-Echeverría, C, Weissleder, R, Mahmood, U, Cantley, LC & Wong, KK 2008, 'Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers', Nature Medicine, vol. 14, no. 12, pp. 1351-1356. https://doi.org/10.1038/nm.1890
Engelman, Jeffrey A. ; Chen, Liang ; Tan, Xiaohong ; Crosby, Katherine ; Guimaraes, Alexander ; Upadhyay, Rabi ; Maira, Michel ; McNamara, Kate ; Perera, Samanthi A. ; Song, Youngchul ; Chirieac, Lucian R. ; Kaur, Ramneet ; Lightbown, Angela ; Simendinger, Jessica ; Li, Timothy ; Padera, Robert F. ; García-Echeverría, Carlos ; Weissleder, Ralph ; Mahmood, Umar ; Cantley, Lewis C. ; Wong, Kwok Kin. / Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. In: Nature Medicine. 2008 ; Vol. 14, No. 12. pp. 1351-1356.
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