Functional and omics-based rationale for the induction of BRCAness by androgen receptor pathway inhibitors to sensitize prostate cancer to PARP inhibition, regardless of HRR status

ABSTRACT: Two PARP inhibitors (PARPi) olaparib and talazoparib have been approved in combination with novel-hormonal-therapies (NHTs) for the treatment of metastatic castration resistant prostate cancer (mCRPC) – in Europe independent of the HRR status. However, the underlying mechanism of action in HRR negative patients is still not fully understood. In the current study, we revealed that combining PARPi (olaparib or talazoparib) with NHTs (abiraterone, enzalutamide, or apalutamide) significantly reduced cell survival in HS LNCaP and CR DU145 and 22RV1 PCa cell lines. While PDOs did not respond to olaparib alone, talazoparib mono-treatment reduced survival >2-fold in one LN-metastatic PDO and marginally (1.1-fold) in the other two. NHTs using abiraterone, enzalutamide or apalutamide all significantly reduced survival in the two LN-metastatic PDOs but were ineffective in the bone-metastatic PDOs. Importantly, the combination of any of the PARPi with any of the NHTs demonstrated significantly greater cytotoxic effects across all PDOs. None of these PDOs displayed a profile typically linked to BRCAness, as identified by the HRDetect score. Sequential (NHT followed by PARPi) and simultaneous treatment strategies yielded comparable results. Transcriptomic and immunoblotting analyses revealed that NHTs downregulate the homologous recombination repair gene RAD51, inducing a "BRCAness-like" phenotype characterized by reduced RAD51 foci formation at DNA double-strand break (DSB) sites, and sensitizing tumor cells to PARPi. Consistently, among the LN-metastatic TSCs, 67% exhibited a substantial reduction in DSB repair capacity when treated with the combined regime compared to monotherapies. Further, proteomic analyses indicate that olaparib may suppress metastasis by inhibiting key pro-metastatic pathways, including epithelial-mesenchymal transition and angiogenesis. Collectively, we provide a mechanistic rationale for integrating NHTs with PARPi, regardless of treatment sequence, in treating mPCa patients. NHT induces a BRCAness-like phenotype, rendering cells sensitive to PARPi. Additionally, we establish the potential of PARPi to suppress metastasis in mPCa during the treatment course.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Cancer Cell

DISEASE(S): Prostate Cancer

SUBMITTER: Ayham Moustafa  

LAB HEAD: Prof. Dr. Wael Mansour

PROVIDER: PXD063764 | Pride | 2026-07-10

REPOSITORIES: Pride