Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

Androgen receptor inhibition induces a “BRCAness” state that may be exploited with PARP inhibitors in patients with advanced prostate cancer. Engineering BRCAness and chemotherapeutic sensitivity BRCA mutations impair a double-strand break DNA repair pathway that forces cells to use a PARP-dependent repair pathway. PARP inhibitors are selectively toxic to breast cancers with BRCA mutations, spurring the search for other tumors or ways in which to apply such exquisitely tumor-targeted therapy. Few other tumors have BRCA mutations as commonly as do breast tumors. However, Li et al. found that a common therapy for prostate cancer patients created a BRCA-deficient state that sensitized tumor cells to PARP inhibitors and leveraged this finding into a potential treatment strategy. Noting that the androgen receptor inhibitor enzalutamide decreased the expression of BRCA1 in prostate cancer cells, the authors treated a mouse model of prostate cancer first with enzalutamide and then with the PARP inhibitor olaparib. Sequential treatment of enzalutamide and olaparib suppressed tumor growth in these mice better than either drug by itself or when both drugs were administered at the same time. The results suggest that “BRCAness” could be therapeutically induced to provide more treatment options not only for prostate cancer patients but also for patients with other types of cancers lacking BRCA mutations. 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.