Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Fracionamento da Dose de Radiação , Fatores Reguladores de Interferon/genética , Células-Tronco Neoplásicas/efeitos da radiação , Neoplasias da Próstata/radioterapia , Transcriptoma/efeitos da radiação , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Genótipo , Humanos , Fatores Reguladores de Interferon/metabolismo , Masculino , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fatores de Tempo , Células Tumorais CultivadasRESUMO
A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first-line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion-positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first-line endocrine therapy for PCa patients with diagnosed BRCAness.