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dc.contributor.authorHwang, B.-J.
dc.contributor.authorAdhikary, G.
dc.contributor.authorEckert, R.L.
dc.date.accessioned2019-04-29T19:00:59Z
dc.date.available2019-04-29T19:00:59Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85049886912&doi=10.18632%2foncotarget.25765&partnerID=40&md5=a2ecd2de9f051039e03f65edfe080be7
dc.identifier.urihttp://hdl.handle.net/10713/8928
dc.description.abstractMelanoma patients respond poorly to chemotherapies because they acquire drug resistance. Therapies that can overcome the resistance to inhibitors of the mutated BRAF protein kinase in melanoma are urgently needed. Chk1 protein kinase is a central component of the DNA damage response and plays a crucial role in controlling cell cycle progression. Analyses indicate that low mRNA expression of Chk1 is significantly associated with good overall survival of melanoma patients. To evaluate the effectiveness of Chk1 inhibitors in melanoma therapy, we have generated BRAF inhibitor (PLX4032 or vemurafenib) resistant melanoma cell lines (A375-PLX-R and WM9-PLX-R) from A375 and WM9, respectively. We observe that AKT (protein kinase B) is constitutively activated in A375-PLX-R, but not in WM9-PLX-R cells, suggesting that these cells develop resistance to PLX4032 through different mechanisms. We show that a potent and specific inhibitor of Chk1 (PF477736) is effective in reducing cell viability and colony formation of PLX4032-resistant cells. Even more impressively, PF477736 triggers PLX4032-resistant melanoma cells to regain sensitivity to the PLX4032. Mouse xenograft studies show that treating A375-PLX-R derived tumors with combined PLX4032 and PF477736 significantly reduce tumor growth. Combined treatments with PLX4032 and PF477736 reduce the levels of total Chk1 protein and alter Chk1 phosphorylation at several sites in both PLX4032 sensitive and resistant melanoma cells. Combinatorial treatments with PLX4032 and PF477736 to melanoma cells substantially induce DNA damage and cell death. Our results suggest that Chk1 inhibitors may provide new therapy options for melanoma patients. Copyright Hwang et al.en_US
dc.description.sponsorshipThis work was supported by National Institutes of Health grants R01GM118837 to A-Lien Lu as well as R01-CA184027 and R01-CA211909 to Richard Eckert.en_US
dc.description.urihttps://dx.doi.org/10.18632/oncotarget.25765en_US
dc.language.isoen_USen_US
dc.publisherImpact Journals LLCen_US
dc.relation.ispartofOncotarget
dc.subjectBRAFen_US
dc.subjectChk1en_US
dc.subjectinhibitorsen_US
dc.subject.meshDrug Resistanceen_US
dc.subject.meshMelanomaen_US
dc.titleChk1 inhibition as a novel therapeutic strategy in melanomaen_US
dc.typeArticleen_US
dc.identifier.doi10.18632/oncotarget.25765


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