Synergistic Pharmacodynamic Effects of Gemcitabine and Fibroblast Growth Factor Receptor Inhibitors on Pancreatic Cancer Cell Cycle Kinetics and Proliferation

Abstract

Median survival of pancreatic ductal adenocarcinoma cancer (PDAC) is 6 months, with 9% 5year 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 ψ death =0.798, suggesting synergistic effects. The mechanism-based cell cycle progression model estimated drug interaction coefficient ψ cycle =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.

Highly Reproducible Quantitative Proteomics Analysis of Pancreatic Cancer Cells Reveals Proteome-Level Effects of a Novel Combination Drug Therapy That Induces Cancer Cell Death via Metabolic Remodeling and Activation of the Extrinsic Apoptosis Pathway

“…We tested the hypothesis that the drugs affected cell growth, apoptosis, or both. DAVID and IPA of the proteomics data (above) lend support to the hypothesis, and we evaluated and validated drug-mediated dysregulation in pathways related to cell cycle regulation previously . Cells treated with single-agent BGJ398 or Gem+BGJ398 showed alteration of both cell cycle and apoptotic processes, and numerous proteins were uniquely altered by the combined drug treatment (Figure B, Supplemental Figure S3–S4B), as visualized using the KEGG pathways tool (Supplemental Figure S5).…”

“…The large data set generated here can be further incorporated in future meta-analysis studies and used for modeling-based studies to investigate time-dependent treatment-mediated patterns of protein alteration and to facilitate systems-level pharmacological analysis. Based on this and additional work, the novel drug combination of Gem+BGJ398 appears promising in treating PDAC and merits further investigation.…”

“…To assess the potential synergy between pan-FGFR inhibitor BGJ398 and Gem, MIAPaCa-2 cells were treated in triplicate with the vehicle control, Gem, BGJ398, or combined Gem +BGJ398 (Figure 1A) at drug concentrations representing the individual IC 50 of Gem (7.5 nM) and BGJ398 (2.5 μM). 22 Cells were exposed to the drugs for 24, 48, 72, and 96 h to capture temporal changes in growth and protein expression in parallel (Figure 1A). Although cell numbers increased over 4 days in all groups, cell proliferation was attenuated in the treatment groups (Figure 1B).…”

“…In the current study, we investigated the molecular-level effects and interactions of Gem combined with BGJ398 (infigratinib), a selective pan-Fibroblast Growth Factor receptor (FGFR) inhibitor . BGJ398 has been investigated in multiple cancers in which FGFR alterations (deregulation of expression and abnormal activation) were observed, including bladder and gastric cancers, , malignant rhabdoid tumors, and urothelial carcinoma, and it recently received FDA approval for cholangiocarcinoma. , Deranged FGF/FGFR signaling plays an important role in the growth and invasive properties of pancreatic cancer, , and thus targeting the FGFR pathway in pancreatic cancer could improve the efficacy of Gem-based treatment for pancreatic cancers.…”

Lipocalin 2 may be a key factor regulating the chemosensitivity of pancreatic cancer to gemcitabine

“…Epidemiological data shows that the overall 5-year survival rate of patients with pancreatic cancer is < 7%, and the disease ranks as the fourth and sixth cause of malignant tumor-related deaths in the United States and China, respectively [ 1 ]. Presently, surgical resection followed by adjuvant chemotherapy is still the preferred treatment strategy for pancreatic cancer; however, the success rate of radical resection is only 15–20%, and this can be attributed to a locally advanced stage of the disease or distant metastasis at first diagnosis [ 2 ]. Chemotherapy is an important treatment strategy for improving the prognosis of patients with locally advanced and metastatic pancreatic cancer.…”