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

2018; American Association for Cancer Research; Volume: 24; Issue: 19 Linguagem: Inglês

10.1158/1078-0432.ccr-17-2773

1557-3265

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, Umar Saeed, Eric Sugarman, Clemens Krepler, Patricia Brafford, Katrin Sproesser, Sengottuvelan Murugan, Rajasekharan Somasundaram, Bradley Garman, Bradley Wubbenhorst, Jonathan Woo, Xiangfan Yin, Qin Liu, Dennie T. Frederick, Benchun Miao, Wei Xu, Giorgos C. Karakousis, Xiaowei Xu, Lynn M. Schuchter, Tara C. Mitchell, Lawrence N. Kwong, Ravi K. Amaravadi, Yiling Lu, Genevieve M. Boland, Zhi Wei, Katherine L. Nathanson, Utz Herbig, Gordon B. Mills, Keith T. Flaherty, Meenhard Herlyn, Jerry W. Shay,

Cancer Cells and Metastasis

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 AACRSee related commentary by Teh and Aplin, p. 4629.