PT  - JOURNAL ARTICLE
AU  - Qingxiang Lin
AU  - Zhicheng Qian
AU  - William J Jusko
AU  - Donald E. Mager
AU  - Wen Wee Ma
AU  - Robert M. Straubinger
TI  - Synergistic pharmacodynamic effects of gemcitabine and fibroblast growth factor receptor inhibitors on pancreatic cancer cell cycle kinetics and proliferation
AID  - 10.1124/jpet.120.000412
DP  - 2021 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2020-000412
4099  - http://jpet.aspetjournals.org/content/early/2021/03/22/jpet.120.000412.short
4100  - http://jpet.aspetjournals.org/content/early/2021/03/22/jpet.120.000412.full
AB  - Median survival of pancreatic ductal adenocarcinoma cancer (PDAC) is 6 months, with 9% 5-year survival. Standard-of-care gemcitabine (Gem) provides only modest survival benefit, and combination therapies integrating novel targeted agents could improve outcomes. FGF receptors (FGFR) play important roles in PDAC growth and invasion. Therefore, FGFR inhibitors (FGFRi) merit further investigation. Efficacy of Gem combined with BGJ398, a pan-FGFRi, was investigated in multiple PDAC cell lines exposed to the drugs alone and combined. Cell cycle distribution and cell numbers were quantified over time. Two pharmacodynamic models were developed to investigate Gem/BGJ398 interactions quantitatively: a drug-mediated cell proliferation/death model, and a drug-perturbed cell cycle progression model. The models captured temporal changes in cell numbers, cell cycle progression, and cell death during drug exposure. Simultaneous fitting of all data provided reasonable parameter estimates. Therapeutic efficacy was then evaluated in a PDAC mouse model. Compared to Gem alone, combined Gem+FGFRi significantly down-regulated ribonucleotide-diphosphate reductase large subunit (RRM1), a Gem resistance (GemR) biomarker, suggesting the FGFRi inhibited GemR emergence. The cell proliferation/death pharmacodynamic model estimated the drug interaction coefficient ψdeath =0.798, suggesting synergistic effects. The mechanism-based cell cycle progression model estimated drug interaction coefficient ψcycle =0.647, also suggesting synergy. Thus FGFR inhibition appears to synergize with Gem in PDAC cells and tumors by sensitizing cells to Gem-mediated inhibition of proliferation and cell cycle progression. Significance Statement An integrated approach of quantitative modeling and experimentation was employed to investigate the nature of FGFRi/Gem interaction, and to identify mechanisms by which FGFRi exposure reverses Gem resistance in pancreatic cancer cells. The results show that FGFRi interacts synergistically with Gem to sensitize pancreatic cancer cells and tumors to Gem-mediated inhibition of proliferation and cell cycle progression. Thus addition of FGFRi to standard-of-care Gem treatment could be a clinically-deployable approach to enhance therapeutic benefit to pancreatic cancer patients.