Targeting Src in Mucinous Ovarian Carcinoma

Abstract

PURPOSE Mucinous ovarian carcinomas have a distinct clinical pattern compared to other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of src kinase in pre-clinical models of mucinous ovarian carcinoma. EXPERIMENTAL DESIGN 1302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of src kinase inhibition were tested in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2) using dasatinib-based therapy. RESULTS Patients with advanced-stage mucinous ovarian cancer had significantly worse survival compared to those with serous histology: median overall survival, 1.67 versus 3.41 years, p=0.002; and median survival time after recurrence of 0.53 versus 1.66 years, p<0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting src with dasatinib in vivo showed significant anti-tumor effects in the RMUG-S-ip2 model, but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further demonstrated significant effects on reducing cell viability, increasing apoptosis, and in vivo anti-tumor effects in the RMUG-S-ip2 model. CONCLUSIONS Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting src kinase with combination of dasatinib and oxaliplatin may be an attractive approach in this disease.

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…FGF stimulates SRC proto-oncogene/focal adhesion kinase, SRC/PI3K/Akt, Hedgehog, Notch, transforming growth factor-β and noncanonical WNT signaling cascades and regulates a variety of cellular functions (5,21,22). The nonreceptor tyrosine kinase Src, the downstream target of FGFR, has been reported to serve an important role in chemoresistance in mucinous ovarian cancer (23). Thus, an association between the expression of growth factor pathways and increased resistance to chemotherapy in mucinous ovarian cancer has been implicated.…”

“…A previous review summarized numerous molecular aspects of chemoresistance, including oncogenes (EGFR/PI3K/Akt and WNT), ATP binding cassette (ABC) transporter pumps, EMT and cancer cell stemness (32). Ovarian cancer subtypes are distinct entities, having different responses to chemotherapy (23). Epithelial ovarian cancer is originally classified into two groups based on chemosensitivity.…”

“…Serous and endometrioid ovarian cancers exhibit a hallmark of chemosensitivity, with higher response rates for taxane/platinum-based regimens. By contrast, mucinous and clear cell cancers are primarily resistant to chemotherapies (23). Patients with advanced-stage mucinous ovarian cancer exhibit higher rates of chemoresistance and have poorer survival outcomes compared with those with advanced-stage high-grade serous ovarian cancer (33).…”

“…The WNT inhibitors/antagonists, including vantictumab (anti-FZD) and ipafricept (FZD8-Fc), potentiate taxane-mediated cancer cell death. Furthermore, platinum treatment may induce activation of Src kinase (23). Combination therapy of oxaliplatin with dasatinib, a Src inhibitor, has previously exhibited antitumor effects in a mucinous cancer model (23).…”

Mucinous ovarian cancer: A therapeutic review

“…In preclinical mEOC models, encouraging results have been achieved by targeting Src signaling with dasatinib [135] and KX-01; a novel Src inhibitor and antitubule agent, in synergy with oxaliplatin [136].…”