Advertisement

Targeted Oncology

, Volume 7, Issue 3, pp 173–181 | Cite as

Resistance to targeted therapies in pancreatic neuroendocrine tumors (PNETs): molecular basis, preclinical data, and counteracting strategies

  • Annemilaï Tijeras-Raballand
  • Cindy Neuzillet
  • Anne Couvelard
  • Maria Serova
  • Armand de Gramont
  • Pascal Hammel
  • Eric Raymond
  • Sandrine Faivre
Review
First Online:

Abstract

Management of advanced pancreatic neuroendocrine tumors (PNETs) is challenging. Chemotherapy has remained for decades the only validated therapeutic option, with debated efficacy. Recently, data from two large placebo-controlled phase III trials have demonstrated that targeted therapies directed against receptor of vascular endothelial growth factor (sunitinib) and mammalian target of rapamycin (mTOR) (everolimus) produced clinically significant improvement in patients with advanced PNETs, resulting in a doubling of progression free survival and leading to their FDA approval. However, as more patients have been treated following the approval of those drugs, reports of early progression, and tumor regrowth following initial responses strongly suggested that primary and acquired resistances may limit the efficacy of targeted therapies in PNETs. In this review, we aim to summarize the current knowledge about primary and acquired resistance to targeted therapies, i.e., antiangiogenic agents and mTOR inhibitors, using data available from preclinical and clinical studies in various malignancies. Herein, we also describe how these general mechanisms of resistance may emerge in PNETs in patients treated with sunitinib and everolimus. Overcoming such resistances is likely to be the next challenge for clinicians in advanced PNETs management, warranting seeking for new anticancer strategies.

Keywords

Resistance Pancreatic neuroendocrine tumors Targeted therapies Antiangiogenic agents Sunitinib mTOR Everolimus 
This is a preview of subscription content, log in to check access.

Notes

Conflict of interest

All authors of this manuscript have no conflicts of interest except for Sandrine Faivre, Pascal Hammel and Eric Raymond who were compensated with honorarium from Pfizer and Novartis.

References

  1. 1.
    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513PubMedCrossRefGoogle Scholar
  2. 2.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523PubMedCrossRefGoogle Scholar
  3. 3.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRefGoogle Scholar
  5. 5.
    Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887PubMedCrossRefGoogle Scholar
  6. 6.
    Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370PubMedCrossRefGoogle Scholar
  7. 7.
    Carew JS, Kelly KR, Nawrocki ST (2011) Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol 6(1):17–27PubMedCrossRefGoogle Scholar
  8. 8.
    Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688PubMedCrossRefGoogle Scholar
  9. 9.
    Choi J, Chen J, Schreiber SL, Clardy J (1996) Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273(5272):239–242PubMedCrossRefGoogle Scholar
  10. 10.
    Delbaldo C, Albert S, Dreyer C, Sablin MP, Serova M, Raymond E, Faivre S (2011) Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors. Target Oncol 6(2):119–124PubMedCrossRefGoogle Scholar
  11. 11.
    Couvelard A, Sauvanet A (2008) Gastroenteropancreatic neuroendocrine tumors: indications for and pitfalls of frozen section examination. Virchows Arch 453(5):441–448PubMedCrossRefGoogle Scholar
  12. 12.
    Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, Ruszniewski P, Bedossa P (2008) Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res 14(20):6634–6639PubMedCrossRefGoogle Scholar
  13. 13.
    Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (2003) von Hippel–Lindau disease. Lancet 361(9374):2059–2067PubMedCrossRefGoogle Scholar
  14. 14.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8(4):299–309PubMedCrossRefGoogle Scholar
  15. 15.
    Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, Bhowmick D, Lonser RR, Smith R, Rodgers G et al (2003) Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel–Lindau disease. Cancer Res 63(21):7051–7055PubMedGoogle Scholar
  16. 16.
    Gong J, Gan J, Caceres-Cortes J, Christopher LJ, Arora V, Masson E, Williams D, Pursley J, Allentoff A, Lago M et al (2011) Metabolism and disposition of [14C]brivanib alaninate after oral administration to rats, monkeys, and humans. Drug Metab Dispos 39(5):891–903PubMedCrossRefGoogle Scholar
  17. 17.
    Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315(6015):115–122PubMedCrossRefGoogle Scholar
  18. 18.
    Parangi S, O’Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D (1996) Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci U S A 93(5):2002–2007PubMedCrossRefGoogle Scholar
  19. 19.
    Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284(5415):808–812PubMedCrossRefGoogle Scholar
  20. 20.
    Chiu CW, Nozawa H, Hanahan D (2010) Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J Clin Oncol 28(29):4425–4433PubMedCrossRefGoogle Scholar
  21. 21.
    Lopez T, Hanahan D (2002) Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1(4):339–353PubMedCrossRefGoogle Scholar
  22. 22.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744PubMedCrossRefGoogle Scholar
  23. 23.
    Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D (2002) VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1(2):193–202PubMedCrossRefGoogle Scholar
  24. 24.
    Joyce JA, Laakkonen P, Bernasconi M, Bergers G, Ruoslahti E, Hanahan D (2003) Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 4(5):393–403PubMedCrossRefGoogle Scholar
  25. 25.
    Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111(9):1287–1295PubMedGoogle Scholar
  26. 26.
    Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98(18):10314–10319PubMedCrossRefGoogle Scholar
  27. 27.
    Hara S, Oya M, Mizuno R, Horiguchi A, Marumo K, Murai M (2005) Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor. Ann Oncol 16(6):928–933PubMedCrossRefGoogle Scholar
  28. 28.
    Aguirre D, Boya P, Bellet D, Faivre S, Troalen F, Benard J, Saulnier P, Hopkins-Donaldson S, Zangemeister-Wittke U, Kroemer G et al (2004) Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis 9(6):797–805PubMedCrossRefGoogle Scholar
  29. 29.
    Allen E, Walters IB, Hanahan D (2011) Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res 17(16):5299–5310PubMedCrossRefGoogle Scholar
  30. 30.
    Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J et al (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27(18):3027–3035PubMedCrossRefGoogle Scholar
  31. 31.
    Marijon H, Dokmak S, Paradis V, Zappa M, Bieche I, Bouattour M, Raymond E, Faivre S (2011) Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma. J Hepatol 54(5):1073–1078PubMedCrossRefGoogle Scholar
  32. 32.
    Ikezoe T, Nishioka C, Tasaka T, Yang Y, Komatsu N, Togitani K, Koeffler HP, Taguchi H (2006) The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 5(10):2522–2530PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Annemilaï Tijeras-Raballand
    • 1
    • 2
  • Cindy Neuzillet
    • 3
  • Anne Couvelard
    • 4
  • Maria Serova
    • 1
    • 2
  • Armand de Gramont
    • 5
  • Pascal Hammel
    • 3
  • Eric Raymond
    • 2
  • Sandrine Faivre
    • 2
  1. 1.Pre Clinical DepartmentAAREC Filia ResearchBoulogne-BillancourtFrance
  2. 2.Inserm U728-Medical Oncology DepartmentBeaujon University HospitalClichyFrance
  3. 3.Gastroenterology and Pancreatology DepartmentBeaujon University HospitalClichyFrance
  4. 4.Pathology DepartmentBichat University HospitalParis Cedex 18France
  5. 5.AAREC Filia ResearchBoulogne-BillancourtFrance

Personalised recommendations

Cite article

Buy options