Inhibition of PLK1 helps to restrict c-Met-induced growth and therapeutic resistance of renal cancer cells.

Acquired therapeutic resistance is a major problem in the treatment of advanced renal cell carcinoma (RCC). The receptor tyrosine kinase (RTK) c-Met is hyperactive in RCC and plays a major role in the survival of tumor cells during therapy-induced oxidative stress. Although c-Met/RTK inhibitor, cabozantinib (cabo), has demonstrated efficacy in the treatment of RCC, therapeutic resistance significantly restricts its effectiveness. Thus, new target molecules and combination therapies need to be explored. Among several cell cycle regulators, Polo-like kinase 1 (PLK1), which is overexpressed in RCC, can play a vital role in cancer progression. In this study, for the first time, we show that the activation of c-Met markedly promotes renal cancer cell growth and proliferation through PLK1. We found that a novel combination treatment with cabo and a PLK1 inhibitor (onvansertib) induces dual-phase cell cycle arrest at both G1 and G2/M checkpoints and impairs RCC cell migration. It induces tumor cell apoptosis by down-regulating the anti-oxidant transcription factor/cytoprotective molecule, Nrf2/HO-1, and inducing oxidative stress. Our results also showed that onvansertib can downregulate ABC transporters that are involved in drug resistance, and it resensitizes cabo-resistant RCC cells to apoptotic cell death. We further confirmed the effectiveness of the combination treatment through 3D spheroid culture as well as tumor xenograft models of RCC. Following combination treatment, there was increased drug-induced cytotoxicity, and markedly reduced tumor growth in vivo. Together, our pre-clinical study identifies that cabo + onvansertib is an effective combination treatment to overcome c-Met-induced therapeutic resistance in RCC with translational potential.