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The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Molecular and functional characterization of reversible-sunitinib-tolerance state in human renal cell carcinoma
Angela Zaccagnino1, Bozhena Vynnytska-Myronovska1, Michael Stöckle1
1Department of Urology and Pediatric Urology, Saarland University, Homburg, Germany.
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.
Insights
Therapy failure in metastatic renal cell carcinoma (mRCC) with sunitinib can be overcome. Drug-tolerant cancer cells reversibly adapt to sunitinib, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Cell Biology
Background:
- Therapy failure with sunitinib (a tyrosine kinase inhibitor) is a significant challenge in metastatic renal cell carcinoma (mRCC).
- Tumor subpopulations can develop transient, non-mutagenic drug-tolerant states, leading to minimal residual disease and relapse.
- Mechanisms of sunitinib tolerance in RCC are not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying sunitinib tolerance in renal cell carcinoma (RCC) cells.
- To characterize the phenotypic and molecular changes associated with sunitinib tolerance.
- To explore the potential for targeting these mechanisms for novel therapeutic strategies.
Main Methods:
- Induction of sunitinib tolerance in 786-O/S and Caki-2/S RCC cell lines through prolonged drug treatment.
- Assessment of drug sensitivity, clonogenicity, and DNA synthesis in tolerant cells.
- Analysis of signaling pathways (c-MET, AXL, p38 kinase, BCL-2), actin cytoskeleton remodeling, and focal adhesion proteins.
- Evaluation of cellular migration and invasion.
- Drug withdrawal experiments to assess the reversibility of the tolerant state.
Main Results:
- Prolonged sunitinib treatment induced a drug-tolerant state in RCC cells, characterized by reduced sensitivity, enhanced clonogenicity, and increased DNA synthesis.
- Sunitinib tolerance involved activation of c-MET and AXL pathways, altered p38 kinase and BCL-2 signaling, and extensive actin cytoskeleton remodeling.
- Drug response, even in sensitive cells, involved actin cytoskeleton changes, boosted migration, and invasion, suggesting cell state transitions rather than pre-existing mutations.
- The drug-tolerant state was transient and reversible upon drug withdrawal, indicating dynamic regulation and phenotypic heterogeneity.
Conclusions:
- Sunitinib tolerance in RCC is a dynamic, reversible phenotypic switch regulated by specific molecular pathways and cellular processes.
- Understanding these reversible mechanisms provides potential therapeutic targets to overcome sunitinib resistance in mRCC.
- Targeting pathways involved in cell state transitions and cytoskeleton dynamics may re-sensitize tumors to sunitinib treatment.
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