search button
Open Access

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

  • Authors:
    • Tanzeel Khan
    • Alan M. Seddon
    • Angus G. Dalgleish
    • Said Khelwatty
    • Nikolaos Ioannou
    • Satvinder Mudan
    • Helmout Modjtahedi

  • View Affiliations

  • Published online on: October 22, 2020     https://doi.org/10.3892/or.2020.7822
  • Pages: 2581-2594

  • Copyright: © Khan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

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.
View Figures
View References

Related Articles

Journal Cover

December-2020
Volume 44 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

  • Journal Metrics
  • Impact Factor: 3.8
  • Ranked Oncology
    (total number of cites)
  • CiteScore: 8.5
  • CiteScore Rank: Q1: #74/404 Oncology
  • Source Normalized Impact per Paper (SNIP): 0.719
  • SCImago Journal Rank (SJR): 0.864
International Symposium on Molecular Medicine Conference Banner
The Cancer Story
World Congress on Advances in Oncology and International Symposium on Molecular Medicine Conference Banner
World Academy Of Sciences Banner
Heyday Road Banner

0

Copy and paste a formatted citation
x
Spandidos Publications style
Khan T, Seddon AM, Dalgleish AG, Khelwatty S, Ioannou N, Mudan S and Modjtahedi H: 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. Oncol Rep 44: 2581-2594, 2020.
APA
Khan, T., Seddon, A.M., Dalgleish, A.G., Khelwatty, S., Ioannou, N., Mudan, S., & Modjtahedi, H. (2020). 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. Oncology Reports, 44, 2581-2594. https://doi.org/10.3892/or.2020.7822
MLA
Khan, T., Seddon, A. M., Dalgleish, A. G., Khelwatty, S., Ioannou, N., Mudan, S., Modjtahedi, H."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". Oncology Reports 44.6 (2020): 2581-2594.
Chicago
Khan, T., Seddon, A. M., Dalgleish, A. G., Khelwatty, S., Ioannou, N., Mudan, S., Modjtahedi, H."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". Oncology Reports 44, no. 6 (2020): 2581-2594. https://doi.org/10.3892/or.2020.7822