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

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

Sci Signal. 2017 May 23;10(480):

Authors: Li L, Karanika S, Yang G, Wang J, Park S, Broom BM, Manyam GC, Wu W, Luo Y, Basourakos S, Song JH, Gallick GE, Karantanos T, Korentzelos D, Azad AK, Kim J, Corn PG, Aparicio AM, Logothetis CJ, Troncoso P, Heffernan T, Toniatti C, Lee HS, Lee JS, Zuo X, Chang W, Yin J, Thompson TC

Abstract
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.

PMID: 28536297 [PubMed - in process]

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