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dc.contributor.authorEngelman, Jeffrey A.
dc.contributor.authorChen, Liang
dc.contributor.authorTan, Xiaohong
dc.contributor.authorCrosby, Katherine
dc.contributor.authorGuimaraes, Alexander R.
dc.contributor.authorUpadhyay, Rabi
dc.contributor.authorMaira, Michel
dc.contributor.authorMcNamara, Kate
dc.contributor.authorPerera, Samanthi A.
dc.contributor.authorSong, Youngchul
dc.contributor.authorChirieac, Lucian R.
dc.contributor.authorKaur, Ramneet
dc.contributor.authorLightbown, Angela
dc.contributor.authorSimendinger, Jessica
dc.contributor.authorLi, Timothy
dc.contributor.authorPadera, Robert F.
dc.contributor.authorGarcía-Echeverría, Carlos
dc.contributor.authorWeissleder, Ralph
dc.contributor.authorMahmood, Umar
dc.contributor.authorCantley, Lewis C.
dc.contributor.authorWong, Kwok-Kin
dc.date.accessioned2019-09-21T03:37:09Z
dc.date.issued2008
dc.identifier.citationEngelman, Jeffrey A, Liang Chen, Xiaohong Tan, Katherine Crosby, Alexander R Guimaraes, Rabi Upadhyay, Michel Maira, et al. 2008. “Effective Use of PI3K and MEK Inhibitors to Treat Mutant Kras G12D and PIK3CA H1047R Murine Lung Cancers.” Nature Medicine 14 (12): 1351–56. https://doi.org/10.1038/nm.1890.
dc.identifier.issn1078-8956
dc.identifier.issn1546-170X
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41384342*
dc.description.abstractSomatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha 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-alpha 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-alpha 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.
dc.language.isoen_US
dc.publisherNature Research
dash.licenseLAA
dc.titleEffective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers
dc.typeJournal Article
dc.description.versionAccepted Manuscript
dc.relation.journalNature Medicine
dash.depositing.authorWeissleder, Ralph::ea07ce19f187d4fab47c56ee97fa5c5a::600
dc.date.available2019-09-21T03:37:09Z
dash.workflow.comments1Science Serial ID 71234
dc.identifier.doi10.1038/nm.1890
dash.source.volume14;12


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