Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma

Document Type

Article

Publication Date

10-1-2018

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 transcrip-tomics 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.

Identifier

85049464512 (Scopus)

Publication Title

Clinical Cancer Research

External Full Text Location

https://doi.org/10.1158/1078-0432.CCR-17-2773

e-ISSN

15573265

ISSN

10780432

PubMed ID

29563139

First Page

4771

Last Page

4784

Issue

19

Volume

24

Grant

CA010815

Fund Ref

National Institutes of Health

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