title: Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer.
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.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Meaghan M
authors.initials: MM
authors.lastname: Broman
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Colin
authors.initials: C
authors.lastname: Carlock
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Elia
authors.initials: E
authors.lastname: Farah
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana. liu8@purdue.edu.|Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D019398:Genes, BRCA1; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D010793:Phthalazines; D010879:Piperazines; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C531550:olaparib