Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer.

Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as "BRCAness" and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients. We found that castration-resistant prostate cancer (CRPC) cells showed increased expression of a set of HR-associated genes, including BRCA1, RAD54L, and RMI2 Although androgen-targeted therapy is typically not effective in CRPC patients, the androgen receptor inhibitor enzalutamide suppressed the expression of those HR genes in CRPC cells, thus creating HR deficiency and BRCAness. A "lead-in" treatment strategy, in which enzalutamide was followed by the PARP inhibitor olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed the growth of prostate cancer xenografts in mice. Thus, antiandrogen and PARP inhibitor combination therapy may be effective for CRPC patients and suggests that pharmaceutically inducing BRCAness may expand the clinical use of PARP inhibitors.

Science signaling. 2017 May 23*** epublish ***

Likun Li, Styliani Karanika, Guang Yang, Jiangxiang Wang, Sanghee Park, Bradley M Broom, Ganiraju C Manyam, Wenhui Wu, Yong Luo, Spyridon Basourakos, Jian H Song, Gary E Gallick, Theodoros Karantanos, Dimitrios Korentzelos, Abul Kalam Azad, Jeri Kim, Paul G Corn, Ana M Aparicio, Christopher J Logothetis, Patricia Troncoso, Timothy Heffernan, Carlo Toniatti, Hyun-Sung Lee, Ju-Seog Lee, Xuemei Zuo, Wenjun Chang, Jianhua Yin, Timothy C Thompson

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA., Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA., ORBIT (Oncology Research for Biologics and Immunotherapy Translation), The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA., Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. .