Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma

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 MuruganRajasekharan 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 Nathanson, Utz Herbig, Gordon B. Mills, Keith T. Flaherty, Meenhard Herlyn, Jerry W. Shay

Research output: Contribution to journalArticle

10 Scopus citations

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 transcrip-tomics 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.

Original languageEnglish (US)
Pages (from-to)4771-4784
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number19
DOIs
StatePublished - Oct 1 2018

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhang, G., Wu, L. W., Mender, I., Barzily-Rokni, M., Hammond, M. R., Ope, O., Cheng, C., Vasilopoulos, T., Randell, S., Sadek, N., Beroard, A., Xiao, M., Tian, T., Tan, J., Saeed, U., Sugarman, E., Krepler, C., Brafford, P., Sproesser, K., ... Shay, J. W. (2018). Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. Clinical Cancer Research, 24(19), 4771-4784. https://doi.org/10.1158/1078-0432.CCR-17-2773