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Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 24(19)
- Publication Year :
- 2017
-
Abstract
- 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
- Subjects :
- 0301 basic medicine
Cancer Research
Telomerase
Programmed cell death
Article
Transcriptome
03 medical and health sciences
Therapeutic approach
Mice
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Promoter Regions, Genetic
Melanoma
Thionucleosides
business.industry
Cancer
Deoxyguanosine
Telomere
medicine.disease
030104 developmental biology
Oncology
Apoptosis
Drug Resistance, Neoplasm
Mutation
Cancer research
business
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 24
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....f1f96991f0b5033a10135101411694d3