Synergistic growth inhibition of human pancreatic cancer cells following treatment with a combination of ErbB family blocker afatinib and IGF-IR inhibitor NVP-AEW541
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Ioannou, Nikolaos, Seddon, Alan / M, Dalgleish, Angus, Mackintosh, David and Modjtahedi, Helmout (2013) Synergistic growth inhibition of human pancreatic cancer cells following treatment with a combination of ErbB family blocker afatinib and IGF-IR inhibitor NVP-AEW541. BMC Cancer, 13. pp. 41-52. ISSN 1471-2407
Abstract
Aberrant expression the insulin-like growth factor receptor (IGF-IR) has been reported in a variety of human cancers and has been associated with increased cell proliferation, reduced apoptosis, invasion and metastasis as well as resistance to the HER targeted therapy. We have reported recently the superiority of afatinib, an irreversible erbB family blocker, compared to the anti-EGFR monoclonal antibody (mAb) ICR62 and erlotinib in inhibiting the growth of seven human pancreatic tumour cells and in reducing signalling via the EGFR pathway. Here, we investigated the sensitivity of the same panel of cancer cell lines to treatment with NVP-AEW541, an IGF-IR tyrosine kinase inhibitor, used alone or in combination with ICR62, afatinib and cytotoxic agents. All pancreatic cancer cell lines were found to be IGF-IR positive. At concentrations above 5μM, NVP-AEW541 inhibited completely the growth of the majority of the pancreatic cancer cell lines with IC50 values ranging from 342nM (FA6) to 2.73μM (PT45). In addition, NVP-AEW541 inhibited completely the IGF-I, IGF-II and Insulin induced phosphorylation of IGF-IR and AKT in the NVP-AEW541sensitive FA6 cells but not in BXPc-3 cells (IC50=1.54µM). NVP-AE541 treatment increased the proportion of cells in the G0/G1 and/or sub-G1 phase of the cell cycle in the majority of cell lines. Only afatinib inhibited both the EGF and NRG-I induced tyrosine phophorylation of EGFR and HER-3 in BxPC-3 cells. Interestingly, of various combinations of two agents, treatment with a combination of NVP-AEW541 and afatinib was superior and induced the synergistic growth inhibition of the majority of pancreatic cancer cells. Our results indicate that co-targeting of the erbB family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and could be a useful therapeutic strategy in IGF-IR and HER positive pancreatic cancer.
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| Keywords: | EGFR, IGF-IR, NVP-AEW541, pancreatic cancer |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/7562 |