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.
|Number of pages||11|
|Journal||Molecular Cancer Therapeutics|
|State||Published - Mar 2017|
Bibliographical noteFunding Information:
The study is supported by NIH grants R01CA157429 (X. Liu), R01CA192894 (X. Liu), R01CA196835 (X. Liu), and NIHR01 CA196634 (X. Liu), ACS grant RSG-13-073 (to X. Liu), and NIH grant P30CA023168 (Purdue University Center for Cancer Research).
© 2017 AACR.
ASJC Scopus subject areas
- Cancer Research