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Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma

Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma

Gao Zhang, Lawrence W Wu, Ilgen Mender, Michal Barzily-Rokni, Marc R Hammond, Omotayo Ope, Chaoran Cheng, Themistoklis Vasilopoulos, Sergio Randell, Norah Sadek, Aurelie Beroard, Min Xiao, Tian Tian, Jiufeng Tan, etc.

Clin Cancer Res. 2018 Oct 1;24(19):4771-4784.

PMID: 29563139

Abstract:

Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients.Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcriptomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG.Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL.Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance. Clin Cancer Res; 24(19); 4771-84. ©2018 AACR See related commentary by Teh and Aplin, p. 4629.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP789617	6-Thio-2′-Deoxyguanosine		789-61-7	Price

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