表征晚期前列腺癌中PARP抑制剂治疗联合方案的反应

Background: Combining poly (ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPi) has improved advanced prostate cancer management but questions remain including 1) where in the clinical treatment paradigm will these combinations fare best? 2) what underlies the efficacy of these combinations? and 3) what else may be more effective in combination with a PARPi? Here, we address these questions to advance the utility of PARP inhibition. Methods: LNCaP (CSPC), C4-2B (CRPC), MDVR (enzalutamide-resistant C4-2B derivative), and AbiR (abiraterone-resistant C4-2B derivative) served as models of different advanced prostate cancer indications. Viability assays, microscopy, western blots and RNA-sequencing were used to investigate response to treatment. Results: Data suggest prior exposure to an ARPi does not preclude benefit from combination treatment, but that the effect is greatest in ARPi-naïve cells. Despite a decrease in cellular viability, morphology of treated cells reveals a largely cytostatic response. Transcriptomic analysis and western blots suggest current hypotheses explaining the mechanism of combination efficacy may be incomplete, as findings do not support that ARPis induce significant BRCAness nor that PARPis reduce AR activity. Given that PARPi and ARPi combination may be less effective post ARPi exposure, we sought an alternative which may be more effective in this setting. Our work suggests that PARPis induce a robust, ATM-driven DNA damage response, and that co-targeting ATM elicits a synergistic reduction in cellular viability. Co-inhibition of ATM and PARP is much more effective than ARPi containing combinations in models of ARPi-resistant CRPC. Conclusions: Current results suggest that 1) PARPi and ARPi combinations may be most effective earlier in the treatment paradigm, 2) more work is needed to understand PARPi and ARPi combination efficacy, and 3) ATM inhibition may be better in combination with a PARPi in more advanced settings. Future efforts will be directed at better understanding how these drugs work together and when best to administer them given the rapidly evolving prostate cancer treatment landscape.