Targeted Oncology

, Volume 6, Issue 2, pp 119–124 | Cite as

Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors

  • Catherine Delbaldo
  • Sébastien Albert
  • Chantal Dreyer
  • Marie-Paule Sablin
  • Maria Serova
  • Eric Raymond
  • Sandrine Faivre
Review

Abstract

In the quest for personalized medicine, only a few biological parameters are routinely used to select patients prior to the initiation of anticancer targeted therapies, including mTOR inhibitors. Identifying biological factors that may predict efficacy or resistance to mTOR inhibitors represents an important challenge since rapalogs may exert antitumor effects through multiple mechanisms of action. Despite the fact that no such a factor is currently available, several molecular patterns are emerging, correlating with sensitivity and/or resistance to rapalogs. While activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, overexpression of cyclin D1, and functional apoptosis seem to sensitize tumor cells to rapalogs, Bcl2 overexpression or KRAS mutations are reported to be associated with resistance to mTOR inhibitors in several preclinical models. Translational research aimed at validating those parameters in clinical trials is ongoing.

Keywords

Sensitivity Resistance Rapalogs Rapamycin Everolimus mTOR Bcl2 PTEN KRAS mutation 

Notes

Conflict of interest statement

No funds were received in support of this study.

References

  1. 1.
    Albert S, Serova M, Dreyer C et al (2010) New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Expert Opin Investig Drugs 19:919–930PubMedCrossRefGoogle Scholar
  2. 2.
    Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688PubMedCrossRefGoogle Scholar
  3. 3.
    Le Tourneau C, Faivre S, Serova M et al (2008) mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? Br J Cancer 99:1197–1203PubMedCrossRefGoogle Scholar
  4. 4.
    Faivre S, Raymond E (2008) Mechanism of action of rapalogues: the antiangiogenic hypothesis. Expert Opin Investig Drugs 17:1619–1621PubMedCrossRefGoogle Scholar
  5. 5.
    O’Donnell A, Faivre S, Burris HA 3rd et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595PubMedCrossRefGoogle Scholar
  6. 6.
    Neshat MS, Mellinghoff IK, Tran C et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98:10314–10319PubMedCrossRefGoogle Scholar
  7. 7.
    Noh WC, Mondesire WH, Peng J et al (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10:1013–1023PubMedCrossRefGoogle Scholar
  8. 8.
    Grunwald V, DeGraffenried L, Russel D et al (2002) Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 62:6141–6145PubMedGoogle Scholar
  9. 9.
    Hara S, Oya M, Mizuno R et al (2005) AKT activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an AKT inhibitor. Ann Oncol 16:928–933PubMedCrossRefGoogle Scholar
  10. 10.
    Hay N (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8:179–183PubMedCrossRefGoogle Scholar
  11. 11.
    Wang X, Yue P, Kim YA et al (2008) Enhancing mammalian target of rapamycin (mTOR)—targeted cancer therapy by preventing mTOR/Raptor inhibition-initiated, mTOR/Rictor-Independent Akt Activation. Cancer Res 68:7409–7418PubMedCrossRefGoogle Scholar
  12. 12.
    Dibble CC, Manning BD (2009) A molecular link between AKT regulation and chemotherapeutic response. Cancer Cell 16:178–180PubMedCrossRefGoogle Scholar
  13. 13.
    Fuchs BC, Fujii T, Dorfman JD et al (2008) Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to Epidermal Growth Factor receptor inhibition in human hepatoma cells. Cancer Res 68:2391–2399PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496PubMedCrossRefGoogle Scholar
  15. 15.
    Di Nicolantonio F et al (2010) Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 20:2858–2866CrossRefGoogle Scholar
  16. 16.
    Witzig TE, Geyer SM, Ghobrial I et al (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356PubMedCrossRefGoogle Scholar
  17. 17.
    Hess G, Herbrecht R, Romaguera J et al (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829PubMedCrossRefGoogle Scholar
  18. 18.
    Figlin RA, de Souza P, McDermott D et al (2009) Analysis of PTEN and HIF-1a and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-a. Cancer 115:3651–3660PubMedCrossRefGoogle Scholar
  19. 19.
    Bae-Jump VL, Zhou C, Boggess JF et al (2010) Rapamycin inhibits cell proliferation in type I and type II endometrial carcinomas: a search for biomarkers of sensitivity to treatment. Gynecol Oncol 119:579–585PubMedCrossRefGoogle Scholar
  20. 20.
    Yu K, Toral-Barza L, Discafani C et al (2001) mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249–258PubMedCrossRefGoogle Scholar
  21. 21.
    Yang L, Clarke MJ, Carlson BL et al (2008) PTEN loss does not predict for response to RAD001 (Everolimus) in a glioblastoma orthotopic xenograft test panel. Clin Cancer Res 14:3993–4001PubMedCrossRefGoogle Scholar
  22. 22.
    Raymond E, Alexandre J, Faivre S et al (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347PubMedCrossRefGoogle Scholar
  23. 23.
    Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281PubMedCrossRefGoogle Scholar
  24. 24.
    Raymond E, Dahan L, Raoul JL et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513PubMedCrossRefGoogle Scholar
  25. 25.
    Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523PubMedCrossRefGoogle Scholar
  26. 26.
    Aguirre D et al (2004) Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis 9:797–805PubMedCrossRefGoogle Scholar
  27. 27.
    Majumder PK, Febbo PG, Bikoff R et al (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601PubMedCrossRefGoogle Scholar
  28. 28.
    Aissat N, Le Tourneau C, Ghoul A et al (2008) Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines. Cancer Chemother Pharmacol 62:305–313PubMedCrossRefGoogle Scholar
  29. 29.
    Wangpaichitr M, Wu C, You M et al (2008) Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 591:124–127PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Catherine Delbaldo
    • 1
  • Sébastien Albert
    • 1
  • Chantal Dreyer
    • 1
  • Marie-Paule Sablin
    • 1
  • Maria Serova
    • 1
  • Eric Raymond
    • 1
  • Sandrine Faivre
    • 1
    • 2
  1. 1.Paris Nord Val de Seine University HospitalsParisFrance
  2. 2.Service Inter-Hospitalier de Cancérologie, Laboratoire de Pharmacobiologie des Anticancereux (RayLab), U 728 Inserm Université Paris VIIHôpital BeaujonClichyFrance

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