Targeting the TLK1-Nek1-Mediated Activation of YAP1 Attenuates PD-L1 and Atinflammation Set for Prostate Cancer Immunoevasion

For nearly a century, fundamental observations have demonstrated that prostate cancer (PCa) cells almost always require androgen receptor (AR) stimulation for sustained proliferation, leading to focused efforts to disrupt this pathway. Similarly, efforts have concentrated on understanding AR-driven processes in the context of elevated expression of its target genes, while significantly less emphasis has been placed on the products that become overexpressed when AR signaling is suppressed. Treatment with androgen receptor signaling inhibitors (ARSIs) results in increased expression of the TLK1B splice variant through translational derepression driven by compensatory mTOR activation and subsequent activation of the TLK1NEK1ATRChk1 and NEK1YAP1 pathways. This eventually leads first to pro-survival quiescence and then to adaptation to androgen deprivation therapy (ADT) and progression to castration-resistant PCa (CRPC). This constitutes a novel liability for PCa that we have targeted for several years with new approaches. In this study, we employed immunocompetent mice treated with enzalutamide, atezolizumab (atez), and/or J54 to investigate the immunological implications of this ADT liability and the potential effect of TLK1 axis inhibition in exploiting this feature. Our findings indicate that this liability includes the presentation of an overall immunologically cold tumor—typical for the majority of PCa cases—when managed by ADT, which is inherently transformed into a hot tumor that responds to immune checkpoint blockade (ICB): atez and TLK1i combination treatment. A combination of ICB and TLKi could serve as a potential therapeutic strategy to prevent progression to CRPC in PCa patients.