TY - JOUR
T1 - Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma
AU - Zhang, Gao
AU - Wu, Lawrence W.
AU - Mender, Ilgen
AU - Barzily-Rokni, Michal
AU - Hammond, Marc R.
AU - Ope, Omotayo
AU - Cheng, Chaoran
AU - Vasilopoulos, Themistoklis
AU - Randell, Sergio
AU - Sadek, Norah
AU - Beroard, Aurelie
AU - Xiao, Min
AU - Tian, Tian
AU - Tan, Jiufeng
AU - Saeed, Umar
AU - Sugarman, Eric
AU - Krepler, Clemens
AU - Brafford, Patricia
AU - Sproesser, Katrin
AU - Murugan, Sengottuvelan
AU - Somasundaram, Rajasekharan
AU - Garman, Bradley
AU - Wubbenhorst, Bradley
AU - Woo, Jonathan
AU - Yin, Xiangfan
AU - Liu, Qin
AU - Frederick, Dennie T.
AU - Miao, Benchun
AU - Xu, Wei
AU - Karakousis, Giorgos C.
AU - Xu, Xiaowei
AU - Schuchter, Lynn M.
AU - Mitchell, Tara C.
AU - Kwong, Lawrence N.
AU - Amaravadi, Ravi K.
AU - Lu, Yiling
AU - Boland, Genevieve M.
AU - Wei, Zhi
AU - Nathanson, Katherine
AU - Herbig, Utz
AU - Mills, Gordon B.
AU - Flaherty, Keith T.
AU - Herlyn, Meenhard
AU - Shay, Jerry W.
N1 - Funding Information:
The research was funded by NIH grants P01CA114046, P50CA174523, P50CA70907, 1U54CA224070, DoD PRCRP grant CA150619, AG01228, the Southland Financial Corporation Distinguished Chair in Geriatric Research, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Melanoma Research Foundation; NIH grant 5R01CA136533 to U. Herbig; and by the Tara Miller Foundation to L.M. Schuchter. The support for Shared Resources utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute, CA016672 to the MDACC, and CA142543 to UTSW. Part of this work was performed in laboratories constructed with support from NIH grant C06 RR30414. The authors thank all former and current lab members for comments and helpful discussions; J. Hayden and F. Keeney (Wistar Microscopy Facility), C. Chang, S. Billouin, and T. Nguyen (Wistar Genomics Facility), J.S. Faust (Wistar Flow Cytometry Facility), D. DiFrancesco (Wistar Animal Facility), and F. Chen (Wistar Histotechnology Facility) for technical support; and M.B. Powell for providing human melanoma cells (Stanford University). The authors apologize to those whose work was not cited or mentioned here due to space constraints.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-17-2773
DO - 10.1158/1078-0432.CCR-17-2773
M3 - Article
C2 - 29563139
AN - SCOPUS:85049464512
VL - 24
SP - 4771
EP - 4784
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -