TY - JOUR
T1 - Targeting plk1 to enhance efficacy of olaparib in castration-resistant prostate cancer
AU - Li, Jie
AU - Wang, Ruixin
AU - Kong, Yifan
AU - Broman, Meaghan M.
AU - Carlock, Colin
AU - Chen, Long
AU - Li, Zhiguo
AU - Farah, Elia
AU - Ratliff, Timothy L.
AU - Liu, Xiaoqi
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2017/3
Y1 - 2017/3
N2 - shown promise as a synthetic lethal treatment approach for BRCAmutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cellsmaybe resistant toPARPi. Themechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of theG1-S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. InBRCA1wild-TypeC4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence ofp53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi.
AB - shown promise as a synthetic lethal treatment approach for BRCAmutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cellsmaybe resistant toPARPi. Themechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of theG1-S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. InBRCA1wild-TypeC4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence ofp53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi.
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U2 - 10.1158/1535-7163.MCT-16-0361
DO - 10.1158/1535-7163.MCT-16-0361
M3 - Article
C2 - 28069876
AN - SCOPUS:85014637464
SN - 1535-7163
VL - 16
SP - 469
EP - 479
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 3
ER -