The CDK4/6 inhibitors dephosphorylate RNF26 to stabilize TSC1 and increase the sensitivity of ccRCC to anti-angiogenesis drug

Renal cancer is one of the three most common malignant tumors in the urinary system, and its incidence rate ranks among the top 10 human malignant tumors in the world. It has been reported that the combined use of CDK4/6 inhibitors and mTOR inhibitors has achieved some clinical success in renal cell carcinoma. Therefore, exploring the underlying mechanism of CDK4/6 pathway in cancer cells and the drug interaction of CDK4/6 inhibitors in combination therapy would helpful find new therapeutic strategies for ccRCC. In studies, we intended to explore the mechanism of how CDK4/6 inhibitors increased the protein expression of TSC1 in ccRCC. We demonstrated that the CDK4/6 inhibitors stabilized TSC1 in ccRCC cells. Then, we showed that e3 ligase RNF26 interacted with TSC1 to promote the degradation of TSC1 and activate the mTOR signaling pathway in ccRCC. Treatment of the CDK4/6 inhibitors dephosphorylated RNF26 and decreased the interaction between RNF26 and TSC1 to prevent the degradation of TSC1. Therefore, RNF26 is recognized to be an ideal candidate to modulate the sensitivity of the CDK4/6 inhibitors and mTOR inhibitors in ccRCC.