Pretreatment with LCK Inhibitors Chemosensitizes Cisplatin-Resistant Endometrioid Ovarian Tumors

Abstract

ObjectiveTo evaluate LCK inhibitors (LCKi) as chemosensitizing agents for platinum-resistant endometrioid ovarian carcinoma. MethodsKM Plotter survival data was obtained for endometrioid ovarian cancer based on LCK mRNA expression. Cisplatin resistant endometrioid ovarian carcinoma cell lines were cultured and treated first with LCKi or vehicle, then combination LCKi-cisplatin. Cell viability was assessed via CellTiter-Glo, and apoptosis with Caspase 3/7 Assay. Protein lysates were isolated from treated cells, with{gamma} -H2Ax, a DNA adduct marker, assessed. In vivo study compared mice treated with vehicle or LCK inhibitor followed by LCK inhibitor, cisplatin, or combination therapy. One-way ANOVA and two sample t-test were used to assess statistical significance with GraphPad Prism. ResultsKM plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p=0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p=0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed inhibition of LCK led to increased expression of{gamma} -H2AX. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin leads to significantly slowed tumor growth. ConclusionsWe identified a targetable pathway for chemosensitization of platinum resistant endometrioid ovarian cancer with initial treatment of LCKi followed by co-treatment with LCKi-cisplatin.