PI3K and cancer: lessons, challenges and opportunities

被引：1384

作者：

Fruman, David A. ^{[1
,2
]}

Rommel, Christian ^{[3
]}

机构：

[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA

[2] Univ Calif Irvine, Inst Immunol, Irvine, CA 92697 USA

[3] Amgen Inc, Thousand Oaks, CA 91320 USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2014年 / 13卷 / 02期

基金：

美国国家卫生研究院;

关键词：

PHOSPHOINOSITIDE 3-KINASE P110-ALPHA; SMALL-MOLECULE INHIBITION; PIM KINASE INHIBITORS; B-CELL FUNCTION; G-BETA-GAMMA; BREAST-CANCER; MTOR KINASE; TRANSLATION INITIATION; TUBEROUS SCLEROSIS; MAMMALIAN TARGET;

D O I：

10.1038/nrd4204

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3K delta inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

引用

页码：140 / 156

页数：17

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