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

Clin Cancer Res. 2018 Oct 1;24(19):4771-4784. doi: 10.1158/1078-0432.CCR-17-2773. Epub 2018 Mar 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mice
  • Mutation
  • Promoter Regions, Genetic / genetics*
  • Telomerase / genetics*
  • Telomere / drug effects
  • Telomere / genetics
  • Thionucleosides / pharmacology*

Substances

  • Thionucleosides
  • alpha-2'-deoxythioguanosine
  • Telomerase
  • Deoxyguanosine