Format

Send to

Choose Destination
Clin Cancer Res. 2018 Oct 1;24(19):4771-4784. doi: 10.1158/1078-0432.CCR-17-2773. Epub 2018 Mar 21.

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

Author information

1
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
2
Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas.
3
Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
4
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
5
Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, New Jersey.
6
Abramson Cancer Center and Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania.
7
Division of Translational Medicine and Human Genetics and Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
8
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
9
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
10
Department of Pathology and Laboratory Medicine, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania.
11
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
12
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania. Jerry.Shay@UTSouthwestern.edu herlynm@wistar.org.
14
Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas. Jerry.Shay@UTSouthwestern.edu herlynm@wistar.org.
15
Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

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.

Comment in

PMID:
29563139
PMCID:
PMC6150856
DOI:
10.1158/1078-0432.CCR-17-2773
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center