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Interactions of Everolimus and Sorafenib in Pancreatic Cancer Cells

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Abstract

Everolimus targets the mammalian target of rapamycin, a kinase that promotes cell growth and proliferation in pancreatic cancer. Sorafenib inhibits the Raf-mitogen-activated protein kinase, vascular endothelial growth factor, and platelet-derived growth factor pathways, thus inhibiting cell growth and angiogenesis. Combinations of these two agents are under evaluation for therapy of several cancers. This study examined the effects of everolimus and sorafenib on proliferation of the pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Cell growth inhibition was evaluated in vitro for a range of concentrations of the drugs alone and in combination. Maximum inhibition capacity (I max) and potency (IC50) were determined. The data were analyzed to characterize drug interactions using two mathematical analysis techniques. The Ariens noncompetitive interaction model and Earp model were modified to accommodate alterations in the inhibition parameters of one drug in the presence of another. Sorafenib alone inhibited growth of both cell lines completely (I max = 1), with an IC50 of 5–8 μM. Maximal inhibition by everolimus alone was only 40% (I max = 0.4) in both cell lines, with an IC50 of 5 nM. Slight antagonistic interaction occurred between the drugs; both analytic methods estimated the interaction term Ψ as greater than 1 for both cell lines. The in vitro data for two pancreatic cancer cell lines suggest that a combination of these two drugs would be no more efficacious than the individual drugs alone, consistent with the drug interaction analysis that indicated slight antagonism for growth inhibition.

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REFERENCES

  1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212–36. Epub 2011/06/21.

    Article  PubMed  Google Scholar 

  2. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, 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):1960–6. Epub 2007/04/25.

    Article  PubMed  CAS  Google Scholar 

  3. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6. Epub 2008/09/06.

    Article  PubMed  CAS  Google Scholar 

  4. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157–88. Epub 2007/11/28.

    Article  PubMed  CAS  Google Scholar 

  5. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(27):6771–90. Epub 2005/09/20.

    Article  CAS  Google Scholar 

  6. Altomare DA, Tanno S, De Rienzo A, Klein-Szanto AJ, Skele KL, Hoffman JP, et al. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J Cell Biochem. 2002;87(4):470–6. Epub 2004/01/23.

    Article  PubMed  Google Scholar 

  7. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996;93(8):3636–41. Epub 1996/04/16.

    Article  PubMed  CAS  Google Scholar 

  8. Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog. 1998;21(2):81–6. Epub 1998/03/13.

    Article  PubMed  CAS  Google Scholar 

  9. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501. Epub 2002/07/03.

    Article  PubMed  CAS  Google Scholar 

  10. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40. Epub 2008/10/15.

    Article  PubMed  CAS  Google Scholar 

  11. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109. Epub 2004/10/07.

    Article  PubMed  CAS  Google Scholar 

  12. Ulivi P, Arienti C, Amadori D, Fabbri F, Carloni S, Tesei A, et al. Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines. J Cell Physiol. 2009;220(1):214–21. Epub 2009/03/17.

    Article  PubMed  CAS  Google Scholar 

  13. Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, et al. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res. 2009;15(5):1612–22. Epub 2009/02/19.

    Article  PubMed  CAS  Google Scholar 

  14. Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, et al. RAD001 (everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res. 2007;67(6):2408–13. Epub 2007/03/17.

    Article  PubMed  CAS  Google Scholar 

  15. Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004;64(1):252–61. Epub 2004/01/20.

    Article  PubMed  CAS  Google Scholar 

  16. Stracke S, Ramudo L, Keller F, Henne-Bruns D, Mayer JM. Antiproliferative and overadditive effects of everolimus and mycophenolate mofetil in pancreas and lung cancer cells in vitro. Transplant Proc. 2006;38(3):766–70. Epub 2006/05/02.

    Article  PubMed  CAS  Google Scholar 

  17. Campbell M, Allen WE, Sawyer C, Vanhaesebroeck B, Trimble ER. Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res. 2004;95(4):380–8. Epub 2004/07/10.

    Article  PubMed  CAS  Google Scholar 

  18. Hausenloy DJ, Mocanu MM, Yellon DM. Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning. Cardiovasc Res. 2004;63(2):305–12. Epub 2004/07/14.

    Article  PubMed  CAS  Google Scholar 

  19. Naegele S, Morley SJ. Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress. J Biol Chem. 2004;279(44):46023–34. Epub 2004/08/05.

    Article  PubMed  CAS  Google Scholar 

  20. Lasithiotakis KG, Sinnberg TW, Schittek B, Flaherty KT, Kulms D, Maczey E, et al. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J Investig Dermatol. 2008;128(8):2013–23. Epub 2008/03/08.

    Article  PubMed  CAS  Google Scholar 

  21. Molhoek KR, Brautigan DL, Slingluff Jr CL. Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor rapamycin. J Transl Med. 2005;3:39. Epub 2005/11/01.

    Article  PubMed  Google Scholar 

  22. Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol. 2009;51(4):725–33. Epub 2009/08/12.

    Article  PubMed  CAS  Google Scholar 

  23. Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Halling T, Wellik LE, et al. Sorafenib, a multikinase inhibitor, is effective in vitro against non-hodgkin lymphoma and synergizes with the mTOR inhibitor rapamycin. Am J Hematol. 2012;87(3):277–83. Epub 2011/12/23.

    Article  PubMed  CAS  Google Scholar 

  24. Fraser TR. Lecture on the antagonism between the actions of active substances. Br Med J. 1872;2(618):485–7. Epub 1872/11/02.

    Article  PubMed  CAS  Google Scholar 

  25. Zhao L, Wientjes MG, Au JL. Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res. 2004;10(23):7994–8004. Epub 2004/12/09.

    Article  PubMed  CAS  Google Scholar 

  26. Greco WR, Bravo G, Parsons JC. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 1995;47(2):331–85. Epub 1995/06/01.

    PubMed  CAS  Google Scholar 

  27. Gaddum JH. The quantitative effects of antagonistic drugs. J Physiol. 1937;89:7P.

    Google Scholar 

  28. Ariens EJ, Van Rossum JM, Simonis AM. Affinity, intrinsic activity and drug interactions. Pharmacol Rev. 1957;9(2):218–36. Epub 1957/06/01.

    PubMed  CAS  Google Scholar 

  29. Chakraborty A, Jusko WJ. Pharmacodynamic interaction of recombinant human interleukin-10 and prednisolone using in vitro whole blood lymphocyte proliferation. J Pharm Sci. 2002;91(5):1334–42. Epub 2002/04/27.

    Article  PubMed  CAS  Google Scholar 

  30. Earp J, Krzyzanski W, Chakraborty A, Zamacona MK, Jusko WJ. Assessment of drug interactions relevant to pharmacodynamic indirect response models. J Pharmacokinet Pharmacodyn. 2004;31(5):345–80. Epub 2005/01/27.

    Article  PubMed  CAS  Google Scholar 

  31. Ariens EJ. Molecular basis of drug action. Med Arh. 1964;18:21–38. Epub 1964/08/01. Molekulska osnova djelovanja lijekova.

    PubMed  CAS  Google Scholar 

  32. Ariens EJ, Simonis AM. A molecular basis for drug action. The interaction of one or more drugs with different receptors. J Pharm Pharmacol. 1964;16:289–312. Epub 1964/05/01.

    Article  CAS  Google Scholar 

  33. D’Argrnio DZ, Schumitzky A, Wang X. ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. 2009.

  34. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118(9):3065–74. Epub 2008/08/30.

    PubMed  CAS  Google Scholar 

  35. Zhao L, Au JL, Wientjes MG. Comparison of methods for evaluating drug-drug interaction. Front Biosci (Elite Ed). 2010;2:241–9. Epub 2009/12/29.

    Article  Google Scholar 

  36. Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL, et al. Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 2010;39(4):425–35. Epub 2010/04/27.

    Article  PubMed  CAS  Google Scholar 

  37. Woo S, Pawaskar D, Jusko WJ. Methods of utilizing baseline values for indirect response models. J Pharmacokinet Pharmacodyn. 2009;36(5):381–405. Epub 2009/08/22.

    Article  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

This work was supported in part by NIH grant GM 57980 and by the pilot studies program of the University at Buffalo Clinical and Translational Research Center, and the Buffalo Translational Consortium. The authors thank Ninfa Straubinger, Xu Zhu, and Yang Qu for their assistance with cell culture.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 404 Kapoor Hall, Buffalo, New York, 14214, USA

    Dipti K. Pawaskar, Robert M. Straubinger & William J. Jusko

  2. Department of Cancer Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA

    Robert M. Straubinger

  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA

    Gerald J. Fetterly & Wen W. Ma

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  1. Dipti K. Pawaskar
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  2. Robert M. Straubinger
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  5. William J. Jusko
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Correspondence to William J. Jusko.

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Pawaskar, D.K., Straubinger, R.M., Fetterly, G.J. et al. Interactions of Everolimus and Sorafenib in Pancreatic Cancer Cells. AAPS J 15, 78–84 (2013). https://doi.org/10.1208/s12248-012-9417-7

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  • DOI: https://doi.org/10.1208/s12248-012-9417-7

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