Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma.
Clin Cancer Res, 2018/10/01;24(19):4771-4784.
Zhang G[1], Wu LW[1], Mender I[2], Barzily-Rokni M[3], Hammond MR[3], Ope O[1], Cheng C[4], Vasilopoulos T[5], Randell S[1], Sadek N[1], Beroard A[1], Xiao M[1], Tian T[4], Tan J[1], Saeed U[1], Sugarman E[1], Krepler C[1], Brafford P[1], Sproesser K[1], Murugan S[6], Somasundaram R[1], Garman B[7], Wubbenhorst B[7], Woo J[1], Yin X[1], Liu Q[1], Frederick DT[8], Miao B[8], Xu W[6], Karakousis GC[9], Xu X[10], Schuchter LM[6], Mitchell TC[6], Kwong LN[11], Amaravadi RK[6], Lu Y[12], Boland GM[3], Wei Z[4], Nathanson K[7], Herbig U[5], Mills GB[12], Flaherty KT[8], Herlyn M[13], Shay JW[14, 15]
Affiliations
PMID: 29563139DOI: 10.1158/1078-0432.CCR-17-2773
Impact factor: 13.801
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.
MeSH terms
Animals; Cell Line, Tumor; Deoxyguanosine; Drug Resistance, Neoplasm; Humans; Melanoma; Mice; Mutation; Promoter Regions, Genetic; Telomerase; Telomere; Thionucleosides
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