Fig 2: LCK pathway regulates cisplatin resistance in endometrioid tumors. Downstream of CD55, LCK stimulates expression of DNA repair genes, leading to cisplatin resistance. This targetable pathway identifies LCK inhibitors as adjunctive therapy for platinum resistant ovarian endometrioid cancer

Fig 3: LCK expression is associated with poorer patient survival. Kaplan-Meier progression-free and overall survival curves were obtained from Kaplan-Meier Plotter (KM Plotter: http://kmplot.com/analysis/) for endometrioid ovarian cancer patients who had high versus low tumor mRNA expression of LCK (a, b) prior to therapy

Fig 4: Pretreatment with LCK inhibitor followed by LCKi-cisplatin treatment attenuates tumor burden, and treated tumors indicate decreased P-LCK. NSG mice were injected with CP70-luciferase transfected cells followed by pretreatment with LCKi (6 mice) or vehicle (24 mice) for 14 days. LCKi mice were then co-treated with LCKi and cisplatin, and vehicle mice were randomized to further treatment with vehicle, cisplatin, saracatinib, or combination (6 mice per arm) (a). IVIS imaging was obtained on a weekly basis to assess tumor growth (b). IVIS luminescence was corrected to baseline for each arm and assessed over time (c) and at the experimental endpoint (d). Tumors from NSG mice were extracted, and protein lysates were prepared and immunoblotted for protein expression of P-LCK (Y394) and T-LCK. Fold changes of protein expression are shown in the figure, with values normalized to vehicle control. GAPDH was used as a loading control (e). Two tumors per condition were probed, with at least three technical replicates performed. Mouse body weight at day 7, 21, and 28 were obtained for each arm, with weights shown as fold change from baseline (f)

Fig 5: Cisplatin resistant endometrioid cells treated with LCK inhibitors indicate decreased P-LCK and ovarian endometrioid cells treated with LCK inhibitor indicate increased DNA double strand breaks. Cisplatin resistant ovarian endometrioid cancer cells (CP70) were treated with DMSO, LCK inhibitor saracatinib (Sar) or PP2 at indicated doses for 48 h. Protein lysates were then immunoblotted for phosphorylated LCK (P-LCK Y394) and total LCK (T-LCK). Fold changes of protein expression are shown in the figure, with values normalized to vehicle control. GAPDH was used as loading control (a). CP70 cells treated with the indicated varied doses of saracatinib (Sar) were immunoblotted for ?H2AX. Fold changes of protein expression are shown in the figure, with values normalized to vehicle control. GAPDH was used as a loading control (b). Each experiment was performed with at least three technical replicates