Mechanisms, Limitations, and Prospects of PARP Inhibitor Talazoparib and MTH1 Inhibitor Karonudib for Malignant Tumor Therapy

Cancer cells rely heavily on DNA damage repair mechanisms for survival, making the targeting of the DNA damage response (DDR) pathway an important direction for cancer treatment. Novel DDR inhibitors, talazoparib and karonudib, have shown potential anti-tumor effects, but drug resistance and safety issues limit their further application. This review summarizes the mechanism of synthetic lethality triggered by Talazoparib, a PARP inhibitor, in BRCA-deficient breast cancer cells and further explores how nano-talazoparib improves drug tolerability, enhances antitumor activity, and reverses efflux transporter-mediated acquired resistance. Moreover, this article elaborates on the theory of the MTH1 inhibitor karonudib killing cancer cells by inducing accumulation of oxidative DNA damage, and discusses ABCB1-driven intrinsic resistance to karonudib. In addition, this study provides theoretical and experimental support for developing advanced drug delivery systems (DDS) and combination therapy in the cancer treatment realm. Nevertheless, several challenges remain, such as Talazoparib resistance due to restoration of the homologous recombination (HR) pathway in tumor cells and karonudib side effects that have not been fully explored in early clinical studies. Future research should focus on nanoparticle drug delivery systems of Talazoparib and karonudib and their corresponding combination therapy to overcome drug resistance and further enhance their effectiveness in future cancer treatment.