1. Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
- Author
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Rachele Rosati, Elizabeth M. Swisher, Goldie Y. L. Lui, Shogo Shigeta, Grace Durenberger, Robert L. Diaz, Christopher J. Kemp, Tan A. Ince, Carla Grandori, Kay E. Gurley, Reid Shaw, and Russell Moser
- Subjects
0301 basic medicine ,Cancer Research ,Transfection ,Ipatasertib ,Article ,BET inhibitor ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,Humans ,Medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Ovarian Neoplasms ,Gene knockdown ,business.industry ,medicine.disease ,Bromodomain ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Ovarian cancer ,Proto-Oncogene Proteins c-akt ,Adenocarcinoma, Clear Cell ,Transcription Factors - Abstract
Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K–AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.
- Published
- 2021