Abstract
Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K–AKT–mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K–AKT–mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials’ design to identify potential predictive or prognostic biomarkers.
Similar content being viewed by others
References
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72.
Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449(4):395–401.
Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007;451(4):757–62.
The International Agency for Research on Cancer, Bosman FT, Carneiro F. WHO classification of tumours of the digestive system. Lyon: World Health Organization classification; 2010. p. 417
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.
Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604–20.
Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011;29(22):3044–9.
Strosberg JR, Weber JM, Feldman M, Coppola D, Meredith K, Kvols LK. Prognostic validity of the American Joint Committee on Cancer Staging Classification for midgut neuroendocrine tumors. J Clin Oncol. 2013;31(4):420–5.
Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29(17):2372–7.
Panzuto F. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocrine Relat Cancer. 2005;12(4):1083–92.
Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.
Ortolani S, Ciccarese C, Cingarlini S, Tortora G, Massari F. Suppression of mTOR pathway in solid tumors: lessons learned from clinical experience in renal cell carcinoma and neuroendocrine tumors and new perspectives. Future Oncol. 2015;11(12):1809–28.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.
Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655–7.
Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.
Cargnello M, Tcherkezian J, Roux PP. The expanding role of mTOR in cancer cell growth and proliferation. Mutagenesis. 2015;30(2):169–76.
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–84.
Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15(3):155–62.
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87.
Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203.
Corbo V, Beghelli S, Bersani S, Antonello D, Talamini G, Brunelli M, et al. Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries. Ann Oncol. 2011;23(1):127–34.
von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Can Res. 2000;60(16):4573–81.
Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, Della Peruta M, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28(2):245–55.
Poncet G, Villaume K, Walter T, Pourreyron C, Theillaumas A, Lépinasse F, et al. Angiogenesis and tumor progression in neuroendocrine digestive tumors. YJSRE. 2009;154(1):68–77.
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.
Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13.
Ghayouri M, Boulware D, Nasir A, Strosberg J, Kvols L, Coppola D. Activation of the serine/theronine protein kinase Akt in enteropancreatic neuroendocrine tumors. Anticancer Res. 2010;30(12):5063–7.
Shah T, Hochhauser D, Frow R, Quaglia A, Dhillon AP, Caplin ME. Epidermal growth factor receptor expression and activation in neuroendocrine tumours. J Neuroendocrinol. 2006;18(5):355–60.
François RA, Maeng K, Nawab A, Kaye FJ, Hochwald SN, Zajac-Kaye M. Targeting focal adhesion kinase and resistance to mTOR inhibition in pancreatic neuroendocrine tumors. J Natl Cancer Inst. 2015;107(8):djv123.
Wang L, Ignat A, Axiotis CA. Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms. Appl Immunohistochem Mol Morphol. 2002;10(2):139–46.
Zhou C-F, Ji J, Yuan F, Shi M, Zhang J, Liu B-Y, et al. mTOR activation in well differentiated pancreatic neuroendocrine tumors: a retrospective study on 34 cases. Hepatogastroenterology. 2011;58(112):2140–3.
Kasajima A, Pavel M, Darb-Esfahani S, Noske A, Stenzinger A, Sasano H, et al. mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocrine Related Cancer. 2010;18(1):181–92.
Shida T, Kishimoto T, Furuya M, Nikaido T, Koda K, Takano S, et al. Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors. Cancer Chemother Pharmacol. 2009;65(5):889–93.
Catena L, Bajetta E, Milione M, Ducceschi M, Valente M, Dominoni F, et al. Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges. Targ Oncol. 2011;6(2):65–8.
Wang Y, Ozawa A, Zaman S, Prasad NB, Chandrasekharappa SC, Agarwal SK, et al. The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Can Res. 2011;71(2):371–82.
Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA. 2005;102(24):8573–8.
Chiu CW, Nozawa H, Hanahan D. 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. 2010;28(29):4425–33.
Pavel ME, Hassler G, Baum U, Hahn EG, Lohmann T, Schuppan D. Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas. Clin Endocrinol. 2005;62(4):434–43.
Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol. 2016;34(32):1–12.
Zurita AJ. Circulating protein and cellular biomarkers of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol May Suppl abstract. (abstract no. 4079)
Qian ZR, Ter-Minassian M, Chan JA, Imamura Y, Hooshmand SM, Kuchiba A, et al. Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol. 2013;31(27):3418–25.
Li S-C, Essaghir A, Martijn CEC, Lloyd RV, Demoulin J-B, Berg KO, et al. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol. 2013;26(5):685–96.
Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–84.
Lee HW, Ha SY, Roh MS. Altered expression of PTEN and its major regulator microRNA-21 in pulmonary neuroendocrine tumors. Korean J Pathol. 2014;48(1):17.
Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide lar in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656–63.
Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33.
Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968–77.
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.
Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Investig. 2010;120(8):2858–66.
Gallardo A, Lerma E, Escuin D, Tibau A, Oz JMN, Ojeda B, et al. Increased signalling of EGFR and IGF1R, and deregulation of PTEN–PI3K–Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer. 2012;106(8):1367–73.
Li S, Kong Y, Si L, Chi Z, Cui C, Sheng X, et al. Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma. BMC Cancer. 2014;14(1):376.
Zitzmann K, De Toni EN, Brand S, Göke B, Meinecke J, Spöttl G, et al. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology. 2007;85(1):54–60.
Serra S, Zheng L, Hassan M, Phan AT, Woodhouse LJ, Yao JC, et al. The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy. Cancer Research. 2012;72(22):5683–91.
Cros J, Moati E, Raffenne J, Hentic O, Svrcek M, de Mestier L, et al. Gly388Arg FGFR4 polymorphism is not predictive of everolimus efficacy in well-differentiated digestive neuroendocrine tumors. Neuroendocrinology. 2016;103(5):495–9.
Zurita AJ, Khajavi M, Wu H-K, Tye L, Huang X, Kulke MH, et al. Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours. Br J Cancer. 2015;112(7):1199–205.
Grande E, Capdevila J, Castellano D, Teulé A, Durán I, Fuster J, et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann Oncol. 2015;26(9):1987–93.
Meric-Bernstam F, Akcakanat A, Chen H, Do KA, Sangai T, Adkins F, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 2012;18(6):1777–89.
Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98(18):10314–9.
Durán I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95(9):1148–54.
Moreno A, Akcakanat A, Munsell MF, Soni A, Yao JC, Meric-Bernstam F. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocrine Related Cancer. 2008;15(1):257–66.
Gagliano T, Bellio M, Gentilin E, Molè D, Tagliati F, Schiavon M, et al. mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids. Endocr Relat Cancer. 2013;20(4):463–75.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical standards
The manuscript does not contain clinical studies or patient data.
Conflict of interest
EG. has served as advisor and delivered lectures for Novartis, Pfizer, and IPSEN. P.G. T.A-G, and O.M-S declare no conflict of interest related to this publication.
Rights and permissions
About this article
Cite this article
Gajate, P., Alonso-Gordoa, T., Martínez-Sáez, O. et al. Prognostic and predictive role of the PI3K–AKT–mTOR pathway in neuroendocrine neoplasms. Clin Transl Oncol 20, 561–569 (2018). https://doi.org/10.1007/s12094-017-1758-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-017-1758-3