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

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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.<b>Results:</b> We demonstrated the superior efficacy of 6-thio-dG both <i>in vitro</i> and <i>in vivo</i> 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.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(19); 4771-84. ©2018 AACR</i> <i>See related commentary by Teh and Aplin, p. 4629</i>.