| Autor: |
Jerry W. Shay, Meenhard Herlyn, Keith T. Flaherty, Gordon B. Mills, Utz Herbig, Katherine Nathanson, Zhi Wei, Genevieve M. Boland, Yiling Lu, Ravi K. Amaravadi, Lawrence N. Kwong, Tara C. Mitchell, Lynn M. Schuchter, Xiaowei Xu, Giorgos C. Karakousis, Wei Xu, Benchun Miao, Dennie T. Frederick, Qin Liu, Xiangfan Yin, Jonathan Woo, Bradley Wubbenhorst, Bradley Garman, Rajasekharan Somasundaram, Sengottuvelan Murugan, Katrin Sproesser, Patricia Brafford, Clemens Krepler, Eric Sugarman, Umar Saeed, Jiufeng Tan, Tian Tian, Min Xiao, Aurelie Beroard, Norah Sadek, Sergio Randell, Themistoklis Vasilopoulos, Chaoran Cheng, Omotayo Ope, Marc R. Hammond, Michal Barzily-Rokni, Ilgen Mender, Lawrence W. Wu, Gao Zhang |
| Rok vydání: |
2023 |
| Popis: |
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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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