Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells

BMC Cancer

Helmout Modjtahedi²  David Mackintosh²  Angus Dalgleish¹  Alan M Seddon²  Nikolaos Ioannou² 

[1]Department of Cellular and Molecular Medicine, St George’s University of London, London, UK

[2]School of Life Sciences, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK

关键词: Pancreatic cancer;    NVP-AEW541;    Afatinib;    IGF-IR;    EGFR;   

Others  :  1079949
DOI  :  10.1186/1471-2407-13-41

 received in 2012-07-26, accepted in 2013-01-28,  发布年份 2013

【 摘 要 】

Background

Aberrant expression and activation of the IGF-IR have been reported in a variety of human cancers and have been associated with resistance to HER targeted therapy. In this study, we investigated the effect of simultaneous targeting of IGF-IR and HER (erbB) family, with NVP-AEW541 and afatinib, on proliferation of pancreatic cancer cells.

Methods

The sensitivity of a panel of human pancreatic cancer cell lines to treatment with NVP-AEW541 used alone or in combination with afatinib, anti-EGFR antibody ICR62, and cytotoxic agents was determined using the Sulforhodamine B colorimetric assay. Growth factor receptor expression, cell-cycle distribution and cell signalling were determined using flow cytometry and western blot analysis.

Results

All pancreatic cancer cell lines were found to be IGF-IR positive and NVP-AEW541 treatment inhibited the growth of the pancreatic cancer cell lines with IC50 values ranging from 342 nM (FA6) to 2.73 μM (PT45). Interestingly, of the various combinations examined, treatment with a combination of NVP-AEW541 and afatinib was superior in inducing synergistic growth inhibition of the majority of pancreatic cancer cells.

Conclusion

Our results indicate that co-targeting of the erbB (HER) family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and encourages further investigation in vivo on their therapeutic potential in IGF-IR and HER positive pancreatic cancers.

【 授权许可】

   
2013 Ioannou et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Cartwright T, Richards DA, Boehm KA: Cancer of the pancreas: are we making progress? a review of studies in the US oncology research network. Cancer Control 2008, 15(4):308-313.
• [2]Stathis A, Moore MJ: Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 2010, 7(3):163-172.
• [3]Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA: A Cancer J Clin 2012, 62(1):10-29.
• [4]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA: A Cancer J Clin 2011, 61(2):69-90.
• [5]Modjtahedi H, Dean C: The receptor for EGF and its ligands: expression, prognostic value and target for therapy in cancer international journal. Oncol 1994, 4:277-296.
• [6]Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 2000, 19(56):6550-6565.
• [7]Nicholson RI, Gee JM, Harper ME: EGFR and cancer prognosis. Eur J Cancer 2001, 37(Suppl 4):S9-S15.
• [8]Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Modjtahedi H: Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer. Front Biosci 2012, 17:2698-2724.
• [9]Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001, 2(2):127-137.
• [10]Überall I, Kolár Z, Trojanec R, Berkovcová J, Hajdúch M: The status and role of ErbB receptors in human cancer. Exp Mol Pathol 2008, 84(2):79-89.
• [11]Hynes NE, MacDonald G: ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 2009, 21(2):177-184.
• [12]Hanahan D, Weinberg Robert A: Hallmarks of cancer: the next generation. Cell 2011, 144(5):646-674.
• [13]Werner H, Shalita-Chesner M, Abramovitch S, Idelman G, Shaharabani-Gargir L, Glaser T: Regulation of the insulin-like growth factor-I receptor gene by oncogenes and antioncogenes: implications in human cancer. Mol Genet Metab 2000, 71(1–2):315-320.
• [14]Samani AA, Yakar S, LeRoith D, Brodt P: The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007, 28(1):20-47.
• [15]Pollak M: The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin Cancer Res 2012, 18(1):40-50.
• [16]Baserga R: Customizing the targeting of IGF-1 receptor. Future Oncol 2009, 5(1):43-50.
• [17]Ouban A, Muraca P, Yeatman T, Coppola D: Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol 2003, 34(8):803-808.
• [18]Tognon CE, Sorensen PH: Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert Opin Ther Targets 2012, 16(1):33-48.
• [19]Ioannou N, Dalgleish AG, Seddon AM, Mackintosh D, Guertler U, Solca F, Modjtahedi H: Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells. Br J Cancer 2011, 105(10):1554-1562.
• [20]GarcIa-EcheverrIa C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro H-G, Cozens R, et al.: In vivo antitumor activity of NVP-AEW541–a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 2004, 5(3):231-239.
• [21]Modjtahedi H, Styles JM, Dean CJ: The human EGF receptor as a target for cancer therapy: six new rat mAbs against the receptor on the breast carcinoma MDA-MB 468. Br J Cancer 1993, 67(2):247-253.
• [22]Solca F: Pharmacology and molecular mechanisms of BIBW2992 a potent irreversible dual EGFR/HER-2 kinase inhibitor of cancer therapy. Target Oncol 2007, 2:s15.
• [23]Chou TC, Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984, 22:27-55.
• [24]Modjtahedi H, Dean C: The binding of HB-EGF to tumor cells is blocked by mAbs which Act as EGF and TGFα antagonists. Biochem Biophys Res Commun 1995, 207(1):389-397.
• [25]Kelley RK, Ko AH: Erlotinib in the treatment of advanced pancreatic cancer. Biologics 2008, 2(1):83-95.
• [26]Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, et al.: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of canada clinical trials group. J Clin Oncol 2007, 25(15):1960-1966.
• [27]Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M: Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (herceptin). J Natl Cancer Inst 2001, 93(24):1852-1857.
• [28]Chakravarti A, Loeffler JS, Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002, 62(1):200-207.
• [29]Jones HE, Goddard L, Gee JMW, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI: Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 2004, 11(4):793-814.
• [30]Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, Rinehart C, Seidel B, Yee D, Arteaga CL, et al.: Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 2008, 118(7):2609-2619.
• [31]Adams TE, McKern NM, Ward CW: Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor. Growth Factors 2004, 22(2):89-95.
• [32]Ahmad T, Farnie G, Bundred NJ, Anderson NG: The mitogenic action of insulin-like growth factor I in normal human mammary epithelial cells requires the epidermal growth factor receptor tyrosine kinase. J Biol Chem 2004, 279(3):1713-1719.
• [33]Baserga R: Targeting the IGF-1 receptor: from rags to riches. Eur J Cancer (Oxford, England: 1990) 2004, 40(14):2013-2015.
• [34]Camirand A, Zakikhani M, Young F, Pollak M: Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of Gefitinib (iressa) in human breast cancer cells. Breast Cancer Res 2005, 7(4):R570-R579. Epub 2005 Apr 2012
• [35]Cunningham MP, Thomas H, Marks C, Green M, Fan Z, Modjtahedi H: Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells. Int J Oncol 2008, 33(5):1107-1113.
• [36]Browne BC, Crown J, Venkatesan N, Duffy MJ, Clynes M, Slamon D, O’Donovan N: Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells. Ann Oncol 2011, 22(1):68-73.
• [37]Moser C, Schachtschneider P, Lang SA, Gaumann A, Mori A, Zimmermann J, Schlitt HJ, Geissler EK, Stoeltzing O: Inhibition of insulin-like growth factor-I receptor (IGF-IR) using NVP-AEW541, a small molecule kinase inhibitor, reduces orthotopic pancreatic cancer growth and angiogenesis. Eur J Cancer 2008, 44(11):1577-1586.
• [38]Piao W, Wang Y, Adachi Y, Yamamoto H, Li R, Imsumran A, Li H, Maehata T, Ii M, Arimura Y, et al.: Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther 2008, 7(6):1483-1493.
• [39]Tomizawa M, Shinozaki F, Sugiyama T, Yamamoto S, Sueishi M, Yoshida T: Insulin-like growth factor-I receptor in proliferation and motility of pancreatic cancer. World J Gastroenterol 2010, 16(15):1854-1858.
• [40]Esparís-Ogando A, Ocaña A, Rodríguez-Barrueco R, Ferreira L, Borges J, Pandiella A: Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells. Ann Oncol 2008, 19(11):1860-1869.
• [41]Kaulfuss S, Burfeind P, Gaedcke J, Scharf JG: Dual silencing of insulin-like growth factor-I receptor and epidermal growth factor receptor in colorectal cancer cells is associated with decreased proliferation and enhanced apoptosis. Mol Cancer Ther 2009, 8(4):821-833.
• [42]Mukohara T, Shimada H, Ogasawara N, Wanikawa R, Shimomura M, Nakatsura T, Ishii G, Park JO, Jänne PA, Saijo N, et al.: Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependent on the level of IRS-1 expression. Cancer Lett 2009, 282(1):14-24.
• [43]Jin Q, Esteva FJ: Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia 2008, 13(4):485-498.
• [44]Baserga R: The decline and fall of the IGF-I receptor. J Cell Physiol 2013, 228(4):675-679.