TY - JOUR
T1 - Targeting BET proteins BRD2 and BRD3 in combination with PI3K-AKT inhibition as a therapeutic strategy for ovarian clear cell carcinoma
AU - Shigeta, Shogo
AU - Lui, Goldie Y.L.
AU - Shaw, Reid
AU - Moser, Russell
AU - Gurley, Kay E.
AU - Durenberger, Grace
AU - Rosati, Rachele
AU - Diaz, Robert L.
AU - Ince, Tan A.
AU - Swisher, Elizabeth M.
AU - Grandori, Carla
AU - Kemp, Christopher J.
N1 - Funding Information:
This project was supported by funding from Cure First, the NCI (U01 CA217883, R01 CA214428, and U54 CA132381), Seattle Tumor Translational Research, and the Rivkin Center for Ovarian Cancer.
Funding Information:
T.A. Ince reported a patent for Application No. 20190071634 (Compositions and methods for culturing cells from normal human tubo-ovarian epithelium and human tubo-ovarian tumors) pending, licensed, and with royalties paid from GLG Parma, Salem, MA/US Biological and a patent for US 8,252,591 and US 8,936,939 (Hormone responsive tissue culture system and uses thereof) issued, licensed, and with royalties paid from GLG Pharma, Salem, MA/US Biological. E.M. Swisher reported grants from the NIH during the conduct of the study. C. Grandori is a full-time employee of SEngine Precision Medicine who is developing novel therapeutics for cancer. C.J. Kemp is a founder and stockholder in SEngine Precision Medicine, which generated some of the data used in this work. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-20-0809
DO - 10.1158/1535-7163.MCT-20-0809
M3 - Article
C2 - 33509905
AN - SCOPUS:85103480321
VL - 20
SP - 691
EP - 703
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 4
ER -
