Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer

TY - JOUR

T1 - Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer

AU - Henningsen, Maike

AU - zu Eulenburg, Christine

AU - Kolarova, Teodora

AU - Qi, Jing Wei

AU - Manivong, Kanthinh

AU - Chalukya, Meenal

AU - Dering, Judy

AU - Anderson, Lee

AU - Ginther, Charles

AU - Meuter, Alexandra

AU - Winterhoff, Boris

AU - Jones, Siân

AU - Velculescu, Victor E

AU - Venkatesan, Natarajan

AU - Rong, Hong-Mei

AU - Dandekar, Sugandha

AU - Udar, Nitin

AU - Jänicke, Fritz

AU - Los, Gerrit

AU - Slamon, Dennis J

AU - Konecny, Gottfried E

N1 - ©2013 AACR

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.

AB - Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.

KW - Apoptosis

KW - BRCA2 Protein

KW - Cell Line, Tumor

KW - DNA Fragmentation

KW - Drug Synergism

KW - Female

KW - Histones

KW - Humans

KW - Indoles

KW - Mutation

KW - Ovarian Neoplasms

KW - Poly(ADP-ribose) Polymerases

KW - Topotecan

KW - Ubiquitin-Protein Ligases

U2 - 10.1158/1535-7163.MCT-12-0813

DO - 10.1158/1535-7163.MCT-12-0813

M3 - SCORING: Journal article

C2 - 23729402

VL - 12

SP - 1002

EP - 1015

JO - MOL CANCER THER

JF - MOL CANCER THER

SN - 1535-7163

IS - 6

ER -