Kucukkaraduman Baris, Turk Can, Fallacara Anna L, Isbilen Murat, Senses Kerem M, Ayyildiz Zeynep O, Akbar Muhammad W, Lotem Michal, Botta Maurizio, Gure Ali O
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
Faculty of Medicine, Department of Medical Microbiology, Lokman Hekim University, Ankara 06510, Turkey.
ACS Med Chem Lett. 2020 Feb 18;11(5):928-932. doi: 10.1021/acsmedchemlett.9b00679. eCollection 2020 May 14.
Melanoma is a highly aggressive cancer with poor prognosis. Although more than 80% of melanomas harbor an activating mutation in genes within the MAPK pathway, which are mutually exclusive, usefulness of therapies targeting MAPK pathway are impeded by innate and/or acquired resistance in most patients. In this study, using melanoma cells, we report the efficacy of a recently developed pyrazolo[3,4-]pyrimidine derived c-Src inhibitor 10a and identify a molecular signature which is predictive of 10a chemosensitivity. We show that the expression of TMED7, PLOD2, XRCC5, and NSUN5 are candidate biomarkers for 10a sensitivity. Although an undifferentiated/mesenchymal/invasive status of melanoma cells is associated with resistance to 10a, we show here for the first time that melanoma cells can be sensitized to 10a via treatment with valproic acid, a histone deacetylase inhibitor.
黑色素瘤是一种侵袭性很强且预后较差的癌症。尽管超过80%的黑色素瘤在丝裂原活化蛋白激酶（MAPK）通路基因中存在相互排斥的激活突变，但在大多数患者中，靶向MAPK通路的疗法因先天性和/或获得性耐药而受到阻碍。在本研究中，我们使用黑色素瘤细胞，报告了一种最近开发的吡唑并[3,4 -]嘧啶衍生的c - Src抑制剂10a的疗效，并确定了一种预测10a化学敏感性的分子特征。我们表明，跨膜内质网蛋白7（TMED7）、赖氨酰羟化酶2（PLOD2）、X射线修复交叉互补蛋白5（XRCC5）和NOP2/Sun RNA甲基转移酶5（NSUN5）的表达是10a敏感性的候选生物标志物。尽管黑色素瘤细胞的未分化/间充质/侵袭状态与对10a的耐药性相关，但我们首次在此表明，黑色素瘤细胞可以通过用组蛋白去乙酰化酶抑制剂丙戊酸处理而对10a敏感。
