Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma
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
Zhang, G; Wu, LW; Mender, I; Barzily-Rokni, M; Hammond, MR; Ope, O; Cheng, C; Vasilopoulos, T; Randell, S; Sadek, N; Beroard, A; Xiao, M; Tian, T; Tan, J; Saeed, U; Sugarman, E; Krepler, C; Brafford, P; Sproesser, K; Murugan, S; Somasundaram, R; Garman, B; Wubbenhorst, B; Woo, J; Yin, X; Liu, Q; Frederick, DT; Miao, B; Xu, W; Karakousis, GC; Xu, X; Schuchter, LM; Mitchell, TC; Kwong, LN; Amaravadi, RK; Lu, Y; Boland, GM; Wei, Z; Nathanson, K; Herbig, U; Mills, GB; Flaherty, KT; Herlyn, M; Shay, JW
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