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

Zhang, Gao; Wu, Lawrence W; Mender, Ilgen; Barzily-Rokni, Michal; Hammond, Marc R; Ope, Omotayo; Cheng, Chaoran; Vasilopoulos, Themistoklis; Randell, Sergio; Sadek, Norah; Beroard, Aurelie; Xiao, Min; Tian, Tian; Tan, Jiufeng; Saeed, Umar; Sugarman, Eric; Krepler, Clemens; Brafford, Patricia; Sproesser, Katrin; Murugan, Sengottuvelan; Somasundaram, Rajasekharan; Garman, Bradley; Wubbenhorst, Bradley; Woo, Jonathan; Yin, Xiangfan; Liu, Qin; Frederick, Dennie T; Miao, Benchun; Xu, Wei; Karakousis, Giorgos C; Xu, Xiaowei; Schuchter, Lynn M; Mitchell, Tara C; Kwong, Lawrence N; Amaravadi, Ravi K; Lu, Yiling; Boland, Genevieve M; Wei, Zhi; Nathanson, Katherine; Herbig, Utz; Mills, Gordon B; Flaherty, Keith T; Herlyn, Meenhard; Shay, Jerry W.
Clin Cancer Res; 24(19): 4771-4784, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29563139

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.
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