Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients.
We tested the cytotoxicity of AL3818 on a panel of 7 human endometrial cancer cell lines expressing either wild-type or mutant FGFR2 and also assessed the in vivo antitumor efficacy in a murine, orthotopic AN3CA endometrial cancer model.
Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p<0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177-3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096-3.696).
Combination of FGFR and AKT inhibition in an FGFR2-mutated endometrial cancer xenograft model enhanced modulation of transcript biomarkers from the PI3K/AKT pathway and tumor growth inhibition.
The aim of this study was to examine the therapeutic potential of a rational drug combination based on the simultaneous targeting of mutant-FGFR2 and mTOR-driven signaling pathways in endometrial cancer cells.
Together these data suggest a potential therapeutic benefit to combining an FGFR inhibitor with standard chemotherapeutic agents in endometrial cancer therapy particularly in patients with FGFR2 mutation positive tumors.
In vitro studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074.
Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.
We also observed a nonsignificant inverse association with rs889312 (MAP3K1) variant carriers [OR = 0.85 (95% CI: 0.68-1.05)] and rs1219648 (FGFR2) variant carriers [OR= 0.86 (95% CI: 0.69-1.06) and endometrial cancer risk.
Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2.