Fibroblast growth factor receptor inhibition synergizes with Paclitaxel and Doxorubicin in endometrial cancer cells.
OBJECTIVE
The fibroblast growth factor (FGF) family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas. Given the identification of activating mutations in the FGF receptor 2 (FGFR2) receptor tyrosine kinase in a subset of endometrial tumors, agents with activity against FGFRs are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Here, we evaluated the effect of FGFR inhibition on the in vitro efficacy of chemotherapy in endometrial cancer cell lines.


METHODS
Human endometrial cancer cell lines with wild-type or activating FGFR2 mutations were used to determine any synergism with concurrent use of the pan-FGFR inhibitor, PD173074, and the chemotherapeutics, doxorubicin and paclitaxel, on cell proliferation and apoptosis.


RESULTS
FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with paclitaxel or doxorubicin showed synergistic activity in the 3 FGFR2 mutant cell lines evaluated. In addition, although nonmutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the cytostatic effect of paclitaxel and doxorubicin in a subset of FGFR2 wild-type endometrial cancer cell lines.


CONCLUSIONS
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.
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
Sara A
SA
Byron
David C
DC
Loch
Pamela M
PM
Pollock
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D009154:Mutation / Q000502:physiology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D004317:Doxorubicin; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017239:Paclitaxel