Reference Detail

Ref Type Journal Article
PMID (19029981)
Authors Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK
Title Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers.
Journal Nature medicine
Vol 14
Issue 12
Date 2008 Dec
Abstract Text Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha 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-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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS G12D lung cancer no benefit BEZ235 Preclinical Actionable In a preclinical study, BEZ235 did not induce tumor shrinkage in mouse lung cancer models carrying KRAS G12D (PMID: 19029981). 19029981
KRAS G12D lung cancer sensitive Selumetinib + BEZ235 Preclinical Actionable In a preclinical study, BEZ235 in combination with Selumetinib (AZD6244) induced tumor shrinkage in mouse lung cancer models carrying KRAS G12D (PMID: 19029981). 19029981
KRAS G12D lung adenocarcinoma sensitive Selumetinib + BEZ235 Preclinical Actionable In a preclinical study, a mouse lung adenocarcinoma model harboring the KRAS G12D mutation treated with a combination of the MEK inhibitor selumetinib (AZD6244) and the PI3K inhibitor BEZ235 resulted in significant tumor regression (PMID: 19029981). 19029981
KRAS G12D lung adenocarcinoma decreased response Selumetinib Preclinical Actionable In a preclinical study, the treatment of a mouse model lung adenocarcinoma harboring the KRAS G12D mutant with selumetinib, a MEK inhibitor, resulted in modest tumor regression (PMID: 19029981). 19029981