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

TitleInduction of telomere dysfunction prolongs disease control of therapy-resistant melanoma
Authors
Issue Date2018
Citation
Clinical Cancer Research, 2018, v. 24, n. 19, p. 4771-4784 How to Cite?
AbstractPurpose: 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.
Persistent Identifierhttp://hdl.handle.net/10722/318718
ISSN
2023 Impact Factor: 10.0
2023 SCImago Journal Rankings: 4.623
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, Gao-
dc.contributor.authorWu, Lawrence W.-
dc.contributor.authorMender, Ilgen-
dc.contributor.authorBarzily-Rokni, Michal-
dc.contributor.authorHammond, Marc R.-
dc.contributor.authorOpe, Omotayo-
dc.contributor.authorCheng, Chaoran-
dc.contributor.authorVasilopoulos, Themistoklis-
dc.contributor.authorRandell, Sergio-
dc.contributor.authorSadek, Norah-
dc.contributor.authorBeroard, Aurelie-
dc.contributor.authorXiao, Min-
dc.contributor.authorTian, Tian-
dc.contributor.authorTan, Jiufeng-
dc.contributor.authorSaeed, Umar-
dc.contributor.authorSugarman, Eric-
dc.contributor.authorKrepler, Clemens-
dc.contributor.authorBrafford, Patricia-
dc.contributor.authorSproesser, Katrin-
dc.contributor.authorMurugan, Sengottuvelan-
dc.contributor.authorSomasundaram, Rajasekharan-
dc.contributor.authorGarman, Bradley-
dc.contributor.authorWubbenhorst, Bradley-
dc.contributor.authorWoo, Jonathan-
dc.contributor.authorYin, Xiangfan-
dc.contributor.authorLiu, Qin-
dc.contributor.authorFrederick, Dennie T.-
dc.contributor.authorMiao, Benchun-
dc.contributor.authorXu, Wei-
dc.contributor.authorKarakousis, Giorgos C.-
dc.contributor.authorXu, Xiaowei-
dc.contributor.authorSchuchter, Lynn M.-
dc.contributor.authorMitchell, Tara C.-
dc.contributor.authorKwong, Lawrence N.-
dc.contributor.authorAmaravadi, Ravi K.-
dc.contributor.authorLu, Yiling-
dc.contributor.authorBoland, Genevieve M.-
dc.contributor.authorWei, Zhi-
dc.contributor.authorNathanson, Katherine-
dc.contributor.authorHerbig, Utz-
dc.contributor.authorMills, Gordon B.-
dc.contributor.authorFlaherty, Keith T.-
dc.contributor.authorHerlyn, Meenhard-
dc.contributor.authorShay, Jerry W.-
dc.date.accessioned2022-10-11T12:24:24Z-
dc.date.available2022-10-11T12:24:24Z-
dc.date.issued2018-
dc.identifier.citationClinical Cancer Research, 2018, v. 24, n. 19, p. 4771-4784-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10722/318718-
dc.description.abstractPurpose: 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.-
dc.languageeng-
dc.relation.ispartofClinical Cancer Research-
dc.titleInduction of telomere dysfunction prolongs disease control of therapy-resistant melanoma-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-17-2773-
dc.identifier.pmid29563139-
dc.identifier.scopuseid_2-s2.0-85049464512-
dc.identifier.volume24-
dc.identifier.issue19-
dc.identifier.spage4771-
dc.identifier.epage4784-
dc.identifier.eissn1557-3265-
dc.identifier.isiWOS:000446207700017-

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