Predictive Gene Signature for Pyrazolopyrimidine Derivative c-Src Inhibitor 10a Sensitivity in Melanoma Cells

Kucukkaraduman B., TÜRK C., Fallacara A. L., Isbilen M., Senses K. M., Ayyildiz Z. O., ...More

ACS MEDICINAL CHEMISTRY LETTERS, vol.11, no.5, pp.928-932, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 11 Issue: 5
  • Publication Date: 2020
  • Doi Number: 10.1021/acsmedchemlett.9b00679
  • Journal Name: ACS MEDICINAL CHEMISTRY LETTERS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE
  • Page Numbers: pp.928-932
  • Keywords: melanoma, c-Src, drug resistance, valproic acid, sensitivity biomarkers, DIFFERENTIATION, EXPRESSION
  • Acibadem Mehmet Ali Aydinlar University Affiliated: No

Abstract

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-d]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, XRCCS, and NSUNS 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.