Synergistic activity of agents targeting growth factor receptors, CDKs and downstream signaling molecules in a panel of pancreatic cancer cell lines and the identification of antagonistic combinations: Implications for future clinical trials in pancreatic cancer
| Autor: | Nikolaos Ioannou, Said Abdullah Khelwatty, Helmout Modjtahedi, Satvinder Mudan, Angus G. Dalgleish, Tanzeel Khan, Alan M. Seddon |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Afatinib pancreatic cancer STAT3 Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine combinational therapy Growth factor receptor Cell Movement Cell Line Tumor tyrosine kinase inhibitors Antineoplastic Combined Chemotherapy Protocols medicine cancer Humans Receptors Growth Factor Dinaciclib Protein Kinase Inhibitors Cell Proliferation Clinical Trials as Topic Ceritinib business.industry Cell Cycle Drug Synergism Articles General Medicine targeted therapy HER family Cyclin-Dependent Kinases Gemcitabine Pancreatic Neoplasms Dasatinib 030104 developmental biology Oncology chemistry Research Design 030220 oncology & carcinogenesis Cancer research Erlotinib Drug Screening Assays Antitumor business Drug Antagonism Tyrosine kinase biological SRC medicine.drug |
| Zdroj: | Oncology Reports |
| ISSN: | 1791-2431 1021-335X |
| Popis: | Pancreatic cancer is one of the most aggressive, heterogeneous and fatal type of human cancers for which more effective therapeutic agents are urgently needed. Here, we investigated the sensitivity of a panel of seven human pancreatic cancer cell lines (HPCCLs) to treatment with various tyrosine kinase inhibitors (TKIs), cyclin‑dependent kinase (CDK) inhibitors, an inhibitor of STAT3 stattic, and a cytotoxic agent gemcitabine both as single agents and in combination. The membranous expression of various receptors and the effect of selected agents on cell cycle distribution, cell signaling pathways and migration was determined using flow cytometry, western blot analysis and scratch wound healing assays, respectively. While the expression of both HER‑3 and HER‑4 was low or negative, the expression of EGFR and HER2 was high or intermediate in all HPCCLs. Of all the agents examined, the CDK1/2/5/9 inhibitor, dinacicilib, was the most potent agent which inhibited the proliferation of all seven HPCCLs with IC50 values of ≤10 nM, followed by SRC targeting TKI dasatinib (IC50 of ≤258 nM), gemcitabine (IC50 of ≤330 nM), stattic (IC50 of ≤2 µM) and the irreversible pan‑HER TKI afatinib (IC50 of ≤2.95 µM). Treatment with afatinib and dasatinib inhibited the ligand‑induced phosphorylation of EGFR and SRC respectively. Statistically significant associations were found between HER2 expression and response to treatment with the ALK/IGF‑IR/InsR inhibitor ceritinib and fibroblast growth factor receptor (FGFR)1/2/3 inhibitor AZD4547, HER3 and IGF‑IR expression and their response to treatment with TKIs targeting HER family members (erlotinib and afatinib), and c‑MET and ALK7 expression and their response to treatment with stattic. Interestingly, treatment with a combination of afatinib with dasatinib and gemcitabine with dasatinib resulted in synergistic tumor growth inhibition in all HPCCLs examined. In contrast, the combination of afatinib with dinaciclib was found to be antagonistic. Finally, the treatment with afatinib, dasatinib and dinaciclib strongly inhibited the migration of all HPCCLs examined. In conclusion, the CDK1/2/5/9 inhibitor dinaciclib, irreversible pan‑HER TKI afatinib and SRC targeting TKI dasatinib were most effective at inhibiting the proliferation and migration of HPCCLs and the combination of afatinib with dasatinib and gemcitabine with dasatinib led to synergistic tumor growth inhibition in all HPCCLs examined. Our results support further investigation on the therapeutic potential of these combinations in future clinical trials in pancreatic cancer. |
| Databáze: | OpenAIRE |
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