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Molecular and Functional Characterization of Reversible-sunitinib-tolerance State in Human Renal Cell Carcinoma

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Journal J Cell Mol Med
Date 2024 May 2
PMID 38693863
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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.

Citing Articles

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

Zaccagnino A, Vynnytska-Myronovska B, Stockle M, Junker K J Cell Mol Med. 2024; 28(9):e18329.

PMID: 38693863 PMC: 11063727. DOI: 10.1111/jcmm.18329.

References
1.
Simon T, Gagliano T, Giamas G . Direct Effects of Anti-Angiogenic Therapies on Tumor Cells: VEGF Signaling. Trends Mol Med. 2017; 23(3):282-292. DOI: 10.1016/j.molmed.2017.01.002. View

2.
Gotink K, Broxterman H, Labots M, de Haas R, Dekker H, Honeywell R . Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011; 17(23):7337-46. PMC: 4461037. DOI: 10.1158/1078-0432.CCR-11-1667. View

3.
Kim M, Kim J, Hong H, Lee S, Lee J, Jung E . Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2015; 35(5):462-78. PMC: 4772854. DOI: 10.15252/embj.201592081. View

4.
Garitano-Trojaola A, Sancho A, Gotz R, Eiring P, Walz S, Jetani H . Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia. Commun Biol. 2021; 4(1):799. PMC: 8233337. DOI: 10.1038/s42003-021-02215-w. View

5.
Zaccagnino A, Vynnytska-Myronovska B, Stockle M, Junker K . Molecular and functional characterization of reversible-sunitinib-tolerance state in human renal cell carcinoma. J Cell Mol Med. 2024; 28(9):e18329. PMC: 11063727. DOI: 10.1111/jcmm.18329. View