Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer.
Likun LiStyliani KaranikaGuang YangJiangxiang WangSanghee ParkBradley M BroomGaniraju C ManyamWenhui WuYong LuoSpyridon BasourakosJian H SongGary E GallickTheodoros KarantanosDimitrios KorentzelosAbul Kalam AzadJeri KimPaul G CornAna M AparicioChristopher L LogothetisPatricia TroncosoTimothy HeffernanCarlo ToniattiHyun-Sung LeeJu-Seog LeeXuemei ZuoWenjun ChangJianhua YinTimothy C ThompsonPublished in: Science signaling (2017)
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.
Keyphrases
- dna damage
- dna repair
- prostate cancer
- oxidative stress
- combination therapy
- end stage renal disease
- cell death
- ejection fraction
- induced apoptosis
- cell cycle arrest
- chronic kidney disease
- poor prognosis
- radical prostatectomy
- genome wide
- type diabetes
- signaling pathway
- gene expression
- high fat diet induced
- drug induced
- adipose tissue
- cell proliferation
- skeletal muscle
- long non coding rna
- metabolic syndrome
- transcription factor
- insulin resistance
- genome wide analysis