Abstract
BackgroundOvarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We discovered that activation of the non-receptor tyrosine kinase Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) promoted cisplatin resistance. Here, we hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Our objective was to assess clinical outcomes associated with increased LCK expression, test our hypothesis of utilizing LCKi as pre-treatment followed by co-treatment with cisplatin in platinum resistant ovarian cancer in vitro, and evaluate our findings in vivo to assess LCKi applicability as a therapeutic agent.ResultsKaplan-Meier (KM) 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 LCKi led to increased expression of phosphorylated H2A histone family X (gamma-H2AX), a marker for DNA damage. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin led to significantly slowed tumor growth.ConclusionsWe identified a strategy to therapeutically target cisplatin resistant endometrioid ovarian cancer leading to chemosensitization to platinum chemotherapy via treatment with LCKi followed by co-treatment with LCKi-cisplatin.
Highlights
Ovarian cancer is the most fatal gynecologic malignancy in the United States
Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) expression is associated with poor patient survival Given the previously described mechanism of cisplatin resistance via the LCK pathway, we hypothesized that increased LCK expression would be associated with worse clinical outcomes
Overall survival is not significantly different between groups, though a non-significant trend toward decreased survival was seen with HR 2.45 (p = 0.41, Fig. 1b). This is supported by gene expression profiling data from Tothill et al that found an over 2-fold increased expression in LCK in ovarian cancer subtypes containing high grade endometrioid cells and associated significantly decreased PFS (p < 0.001) and OS (p < 0.001) in this subtype [16]
Summary
Ovarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Ovarian cancer is the most fatal gynecologic malignancy in the United States, with only a 48 % survival at 5 years after diagnosis [1]. In the 15 % of patients failing standard therapy, disease persists or progresses within the first six months after chemotherapy, indicating platinum-resistant disease. Given the poor prognosis in patients with platinum-resistant disease, identification of chemoresistance pathways is necessary for development of therapies to sensitize resistant ovarian cancer [8]
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