期刊
CANCER DISCOVERY
卷 6, 期 10, 页码 1134-1147出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-0305
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资金
- National Cancer Institute [R35 CA197737, P30 CA0087748, R01CA190642-01A1]
- Starr Cancer Consortium
- Gerstner Foundation
- DFCI-NOVARTIS Drug Discovery Program
- Claudia Adams Barr Program for Innovative Cancer Research
- Stand Up To Cancer (SU2C)
- V foundation (TVF) Scholar Award
- American Society of Clinical Oncology (ASCO) Young Investigator Award
- Peter and Deborah Weinberg Family Fund
- Breast Cancer Research Foundation Tory Burch Award
- Geoffrey Beene Cancer Research Center
- Division Of Physics
- Direct For Mathematical & Physical Scien [1545839] Funding Source: National Science Foundation
PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naive breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers. SIGNIFICANCE: PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. (C) 2016 AACR.
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