FAM107A loss facilitates TTK-OPTN-mediated mitophagy to drive docetaxel resistance in castration-resistant prostate cancer

Docetaxel remains a mainstay in the treatment of prostate cancer; however, docetaxel resistance continues to pose a major challenge and is associated with unfavorable patient outcomes. Efforts to overcome known resistance mechanisms have largely failed to improve survival, often increasing toxicity. In this study, we demonstrated that FAM107A expression is downregulated during the development of docetaxel resistance in prostate cancer, and its overexpression enhances cellular sensitivity to docetaxel both in vitro and in vivo. Transcriptomic analyses identified TTK as a downstream effector, which was further validated in vitro. TTK can activate mitophagy, facilitate the timely clearance of damaged mitochondria, reduce intracellular reactive oxygen species levels, and thereby promote docetaxel resistance. We further confirmed the role of the FAM107A-TTK-mitophagy axis in docetaxel resistance in castration-resistant prostate cancer (CRPC) patients at single-cell resolution. Integrated proteomic profiling and co-immunoprecipitation assays revealed that TTK interacts with OPTN, a key mediator of mitophagy. Finally, we showed that the TTK inhibitor CFI-402257 combined with docetaxel exhibited favorable efficacy and safety in vivo against CRPC. Collectively, our findings revealed for the first time the critical role of the FAM107A-TTK-OPTN mitophagy axis in docetaxel resistance and suggest that targeting this axis may represent a promising therapeutic strategy to overcome docetaxel resistance.