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    Chk1 inhibition as a novel therapeutic strategy in melanoma

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    Author
    Hwang, B.-J.
    Adhikary, G.
    Eckert, R.L.
    Date
    2018
    Journal
    Oncotarget
    Publisher
    Impact Journals LLC
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.18632/oncotarget.25765
    Abstract
    Melanoma 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.
    Sponsors
    This 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.
    Keyword
    BRAF
    Chk1
    inhibitors
    Drug Resistance
    Melanoma
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85049886912&doi=10.18632%2foncotarget.25765&partnerID=40&md5=a2ecd2de9f051039e03f65edfe080be7; http://hdl.handle.net/10713/8928
    ae974a485f413a2113503eed53cd6c53
    10.18632/oncotarget.25765
    Scopus Count
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    UMB Open Access Articles 2018

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