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	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine	14	12	2008 Dec	1351-6	Nat Med

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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 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
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