Molecular and functional characterization of reversible‐sunitinib‐tolerance state in human renal cell carcinoma

Abstract

Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non‐mutagenic drug‐tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib‐tolerant 786‐O/S and Caki‐2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib‐tolerance developed via dynamic processes, including (i) engagement of c‐MET and AXL pathways, (ii) alteration of stress‐induced p38 kinase and pro‐survival BCL‐2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib‐tolerant cell lines led to dramatic fine‐tuning of the actin‐cytoskeleton and boosted cellular migration and invasion, indicating that the drug‐response might depend on cell state transition rather than pre‐existing mutations. The drug‐tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib‐tolerance, providing possible novel therapeutic opportunities in RCC.