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Published on: March 6, 2018
Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer
Jie Li1, Ruixin Wang1, Yifan Kong1
1Department of Biochemistry, Purdue University, West Lafayette, Indiana.
Abstract:
Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic 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 the G1-S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 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. Mol Cancer Ther; 16(3); 469-79. ©2017 AACR.
Insights
Combining Polo-like kinase 1 (Plk1) inhibition with olaparib overcomes drug resistance in castration-resistant prostate cancer (CRPC). This strategy enhances olaparib efficacy in both BRCA-mutant and potentially non-BRCA-mutant CRPC cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Olaparib, a PARP inhibitor (PARPi), shows promise for BRCA-mutant castration-resistant prostate cancer (CRPC).
- However, resistance to PARPi, even in BRCA-mutant cells, is an emerging clinical challenge.
- The mechanisms underlying PARPi resistance remain poorly understood.
Purpose of the Study:
- To investigate the role of Polo-like kinase 1 (Plk1) in PARPi resistance in CRPC.
- To evaluate the efficacy of combining a Plk1 inhibitor (BI2536) with olaparib in CRPC models.
- To elucidate the mechanistic basis for enhanced olaparib sensitivity upon Plk1 inhibition.
Main Methods:
- Utilized BRCA1-deficient (22RV1) and BRCA1 wild-type (C4-2) CRPC cell lines and xenograft models.
- Administered olaparib monotherapy and combination therapy with Plk1 inhibitor BI2536.
- Investigated cell-cycle checkpoint modulation and protein expression, including Plk1 and p53.
Main Results:
- Olaparib monotherapy led to elevated Plk1 expression, attenuating its efficacy by overriding the G1-S checkpoint.
- Combination therapy with BI2536 robustly sensitized olaparib in BRCA1-deficient CRPC cells and xenografts.
- Plk1 inhibition increased olaparib efficacy in BRCA1 wild-type cells, particularly when combined with a p53 inhibitor.
Conclusions:
- Plk1 plays a critical role in mediating olaparib resistance in BRCA-mutant CRPC.
- Combined Plk1 and PARP inhibition represents a viable strategy to overcome resistance in CRPC.
- This approach may extend the benefits of PARPi to non-BRCA-mutant CRPC patient subgroups.
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