Abstract C86: FGFR inhibition potentiates the effect of conventional chemotherapeutic agents in endometrial cancer cells

Abstract

Abstract Endometrial cancer is the most common gynecological malignancy and the fourth most common cancer in women in the United States. Most women present with early stage disease confined to the uterus and thus have a favorable prognosis. However, for the subset of women who present with advanced disease or that recur, prognosis is poor, with a median survival after recurrence of 10 months, reflecting a lack of effective treatment options. We identified activating mutations in the fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinase in 10–15% of endometrial tumors, and hypothesized that FGFR inhibition may be a viable therapeutic option for patients with FGFR2 mutation positive tumors. Indeed, we have shown that treatment of FGFR2 mutation positive endometrial cancer cell lines with PD173074, a pan-FGFR small molecular inhibitor, induces cell death both in vitro and in vivo. We have shown this cell death is caspase-independent, raising the possibility that combination of an FGFR inhibitor with chemotherapeutic agents may exhibit synergistic activity due to their non-redundant mechanisms of action. Moreover, as FGF ligand expression has been associated with chemoresistance and poor prognosis in a number of other cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas, we hypothesized that FGFR inhibition may also sensitize wildtype FGFR2 endometrial cancer cell lines to chemotherapeutic agents. We therefore sought to evaluate whether FGFR inhibition synergizes with conventional chemotherapeutic agents in endometrial cancer. Using combination index and Bliss additivity analysis, we evaluated whether FGFR inhibition potentiated the effect of paclitaxel and doxorubicin in a panel of FGFR2 mutant and non-mutant endometrial cancer cell lines. FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with paclitaxel or doxorubicin showed synergistic activity in all three FGFR2 mutant cell lines. In addition, though non-mutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the effect of paclitaxel and doxorubicin in a subset of FGFR2-wildtype cell lines tested. Together these data suggest a therapeutic benefit to combining an FGFR inhibitor with standard chemotherapeutic agents, and, importantly, this may extend to patients whose tumors possess wildtype FGFR2. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C86.