期刊
JOURNAL OF LIPID RESEARCH
卷 60, 期 4, 页码 747-752出版社
ELSEVIER
DOI: 10.1194/jlr.S092130
关键词
phosphoinositide; insulin signaling; insulin resistance; phosphoinositides; lipid kinases; receptor tyrosine kinases; signal transduction; targeted therapies
资金
- National Institutes of Health [R01 GM120055, R01 CA201303]
- National Cancer Institute [R35 CA197588]
- Burroughs Wellcome Fund Career Award in the Biomedical Sciences
- Harrington Discovery Institute
- Petra Pharmaceuticals
The discovery of the phosphatidylinositol-3-kinase (PI3K) pathway was a major advance in understanding growth factor signaling. The high frequency of PI3K pathway mutations in many cancers has encouraged a new field targeting cancer driver mutations. Although there have been many successes, targeting PI3K itself has proven challenging, in part because of its multiple isoforms with distinct roles. Despite promising preclinical results, development of PI3K inhibitors as pharmacologic anticancer agents has been limited by modest single-agent efficacy and significant adverse effects. If we could overcome these limitations, PI3K inhibitors would be a powerful cancer-fighting tool. Data from phase III clinical trials yields insight into some of the problems with PI3K inhibitors. Recent advances have shed light on the mechanisms of tumor resistance to PI3K inhibitors via feedback pathways that cause elevated insulin levels that then activate the same PI3K pathways that are the targets of inhibition. Improving our understanding of the complex regulatory feedback pathways that activate in response to PI3K inhibition will reveal ways to increase the efficacy of PI3K inhibitors and reduce adverse effects, increasing the usefulness of this class as a treatment option for multiple cancer types.
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