Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma.

Abstract

The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed. In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs. The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient.

• Authors: Matteo Santoni, Francesco Pantano, Consuelo Amantini, Massimo Nabissi, Alessandro Conti, Luciano Burattini, Alice Zoccoli, Rossana Berardi, Giorgio Santoni, Giuseppe Tonini, Daniele Santini, Stefano Cascinu
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1845 Issue 2 Pg. 221-31 (Apr 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24480319 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• temsirolimus
• Everolimus
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Carcinoma, Renal Cell (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (genetics)
• Everolimus
• Gene Expression Regulation, Neoplastic
• Humans
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (genetics)
• Sirolimus (analogs & derivatives, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics)