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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||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|
|PIK3CA H1047R||lung adenocarcinoma||no benefit||Sirolimus||Preclinical||Actionable||In a preclinical study, Sirolimus (rapamycin) failed to inhibit tumor growth in a mouse lung adenocarcinoma model expressing the PIK3CA H1047R mutation (PMID: 19029981).||19029981|
|PIK3CA H1047R||lung cancer||sensitive||Dactolisib||Preclinical||Actionable||In a preclinical study, BEZ235 reduced tumor size in mouse models of lung cancer carrying PIK3CA H1047R (PMID: 19029981).||19029981|
|PIK3CA H1047R||lung adenocarcinoma||sensitive||Dactolisib||Preclinical||Actionable||In a preclinical study, BEZ235 promoted tumor regression in a mouse lung adenocarcinoma model expressing PIK3CA H1047R (PMID: 19029981).||19029981|
|PIK3CA H1047R||lung cancer||no benefit||Sirolimus||Preclinical||Actionable||In a preclinical study, Sirolimus (rapamycin) did not induce tumor shrinkage in mouse lung cancer models carrying PIK3CA H1047R (PMID: 19029981).||19029981|