The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer
Main Article Content
Keywords
Drug resistance, Kidney cancer, Lysosomes, Lysosomal sequestration, Renal cell cancer, Sunitinib resistance, Renal cell carcinoma, VHL mutation
Abstract
Renal cell carcinoma (RCC) is a highly vascularized tumor type, which is often associated with inactivated mutations in the von Hippel-Lindau gene that drives proangiogenic signaling pathways. As such, new therapies for the treatment of RCC have largely been focused on blocking angiogenesis. Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the most frequently used first-line drug for the treatment of RCC. Although treatment with sunitinib improves patient outcome considerably, acquired resistance will emerge in all cases. The molecular mechanisms of resistance to sunitinib are poorly understood, but in the past decade, several of these have been proposed. Lysosomal sequestration of sunitinib was reported as a potential resistance mechanism to sunitinib. In this review, the underlying molecular mechanisms of lysosomal sunitinib sequestration and the potential strategies to overcome this resistance are discussed to be able to further improve the treatment of RCC.
References
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24. Tracy TS, Korzekwa KR, Gonzalez FJ, Wainer IW. Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharmacol. 1999;47:545-552.
25. Molina AM, Feldman DR, Voss MH, Ginsberg MS, Baum MS, Brocks DR, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2012 Apr 1;118(7):1868-76. http://dx.doi.org/10.1002/cncr.26429
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27. https://clinicaltrials.gov/
2. Dall'Oglio MF, Antunes AA, Pompeo AC, Mosconi A, Leite KR, Srougi M. Prognostic relevance of the histological subtype of renal cell carcinoma. Int Braz J Urol. 2008;34(1):3-8.
3. Drucker BJ. Renal cell carcinoma: current status and future prospects. Cancer Treat Rev. 2005;31(7):536-45. http://dx.doi.org/10.1016/j.ctrv.2005.07.009
4. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992-1000. http://dx.doi.org/10.1016/S1470-2045(09)70240-2
5. Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2015 Sep 14. http://dx.doi.org/10.1038/onc.2015.343 [Epub ahead of print]
6. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17(23):7337-46. Erratum in: Clin Cancer Res. 2012 Jan 1;18(1):318.
7. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7(1):85-90. http://dx.doi.org/10.1038/ng0594-85
8. Donalisio da Silva R, Gustafson D, Nogueira L, Werahera PN, Molina WR, Kim FJ. Targeted therapy for metastatic renal carcinoma: an update. J Kidney Cancer VHL. 2014;1(6): 63-73.
9. Blumenthal GM, Cortazar P, Zhang JJ, Tang S, Sridhara R, Murgo A, et al. FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. Oncologist. 2012;17(8):1108-13. http://dx.doi.org/10.1634/theoncologist.2012-0044
10. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23(3):329-36. http://dx.doi.org/10.1038/nbt1068
11. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127-32. http://dx.doi.org/10.1038/nbt1358
12. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(1):16-24. http://dx.doi.org/10.1200/JCO.2005.02.2574
13. Clinical Trials website. SU011248 versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. http://clinicaltrials.gov/ct2/show/results/NCT00083889
14. Morais C. Sunitinib resistance in renal cell carcinoma. J Kidney Cancer VHL. 2014;1(1):1-11.
15. Joosten SC, Hamming L, Soetekouw PM, Aarts MJ, Veeck J, van Engeland M, et al. Resistance to sunitinib in renal cell carcinoma: from molecular mechanisms to predictive markers and future perspectives. Biochim Biophys Acta. 2015;1855(1):1-16. http://dx.doi.org/10.1016/j.bbcan.2014.11.002
16. Gotink KJ, Broxterman HJ, Honeywell RJ, Dekker H, de Haas RR, Miles KM, et al. Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature. Oncoscience. 2014;1(12):844-53.
17. Kazmi F, Hensley T, Pope C, Funk RS, Loewen GJ, Buckley DB, et al. Lysosomal sequestration (trapping) of lipophilic amine (cationic amphiphilic) drugs in immortalized human hepatocytes (Fa2N-4 cells). Drug Metab Dispos. 2013;41(4):897-905. http://dx.doi.org/10.1124/dmd.112.050054
18. Gotink KJ, Rovithi M, de Haas RR, Honeywell RJ, Dekker H, Poel D, et al. Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib. Cell Oncol (Dordr). 2015;38(2):119-29. http://dx.doi.org/10.1007/s13402-015-0218-8
19. Colombo F, Trombetta E, Cetrangolo P, Maggioni M, Razini P, De Santis F, et al. Giant lysosomes as a chemotherapy resistance mechanism in hepatocellular carcinoma cells. PLoS One. 2014;9(12):e114787. http://dx.doi.org/10.1371/journal.pone.0114787
20. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31(5):1095-108. http://dx.doi.org/10.1038/emboj.2012.32
21. Zhitomirsky B, Assaraf YG. Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. Oncotarget. 2015;6(2):1143-56.
22. Wang E, Lee MD, Dunn KW. Lysosomal accumulation of drugs in drug-sensitive MES-SA but not multidrug-resistant MES-SA/Dx5 uterine sarcoma cells. J Cell Physiol. 2000;184(2):263-74. http://dx.doi.org/10.1002/1097-4652(200008)184:2<263::AID-JCP15>3.0.CO;2-F
23. Ellegaard AM, Groth-Pedersen L, Oorschot V, Klumperman J, Kirkegaard T, Nylandsted J, et al. Sunitinib and SU11652 inhibit acid sphingomyelinase, destabilize lysosomes, and inhibit multidrug resistance. Mol Cancer Ther. 2013;12(10):2018-30. http://dx.doi.org/10.1158/1535-7163.MCT-13-0084
24. Tracy TS, Korzekwa KR, Gonzalez FJ, Wainer IW. Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharmacol. 1999;47:545-552.
25. Molina AM, Feldman DR, Voss MH, Ginsberg MS, Baum MS, Brocks DR, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2012 Apr 1;118(7):1868-76. http://dx.doi.org/10.1002/cncr.26429
26. Nowak-Sliwinska P, Weiss A, van Beijnum JR, Wong TJ, Kilarski WW, Szewczyk G, et al. Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition. Cell Death Dis. 2015 Feb 12;6:e1641. http://dx.doi.org/10.1038/cddis.2015.4
27. https://clinicaltrials.gov/
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Published
Jan 21, 2016
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How to Cite
The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer. (2016). Journal of Kidney Cancer and VHL, 2(4), 195-203. https://doi.org/10.15586/jkcvhl.2015.44
Section
Kidney Cancer: Review Articles
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