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

被引：1096

作者：

Engelman, Jeffrey A. ^{[1
,2
]}

Chen, Liang ^{[3
,4
]}

Tan, Xiaohong ^{[3
,4
]}

Crosby, Katherine ^{[5
]}

Guimaraes, Alexander R. ^{[6
,7
]}

Upadhyay, Rabi ^{[6
,7
]}

Maira, Michel ^{[8
]}

McNamara, Kate ^{[3
,4
]}

Perera, Samanthi A. ^{[3
,4
]}

Song, Youngchul ^{[1
]}

Chirieac, Lucian R. ^{[9
]}

Kaur, Ramneet ^{[1
,2
]}

Lightbown, Angela ^{[5
]}

Simendinger, Jessica ^{[5
]}

Li, Timothy

Padera, Robert F. ^{[9
]}

Garcia-Echeverria, Carlos ^{[8
]}

Weissleder, Ralph ^{[6
,7
,10
]}

Mahmood, Umar ^{[6
,7
]}

Cantley, Lewis C. ^{[2
,10
]}

Wong, Kwok-Kin ^{[2
,3
,4
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA

[5] Cell Signaling Technol, Danvers, MA 01923 USA

[6] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA

[7] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA

[8] Novartis Inst Biomed Res, Oncol Dis Area, CH-4057 Basel, Switzerland

[9] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

来源：

NATURE MEDICINE | 2008年 / 14卷 / 12期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nm.1890

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Somatic 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.

引用

页码：1351 / 1356

页数：6