Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma.
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.
Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy. Electronic address: mattymo@alice.it.
Matteo
M
Santoni
Department of Medical Oncology, Campus Bio-Medico University of Rome, via Alvaro del Portillo 200, 00128 Rome, Italy.
Francesco
F
Pantano
School of Pharmacy, Section of Experimental Medicine, University of Camerino, via Madonna delle Carceri 9, 62032 Camerino, Italy.
Consuelo
C
Amantini
School of Pharmacy, Section of Experimental Medicine, University of Camerino, via Madonna delle Carceri 9, 62032 Camerino, Italy.
Massimo
M
Nabissi
Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche, Clinica di Urologia, Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy.
Alessandro
A
Conti
Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy.
Luciano
L
Burattini
Department of Medical Oncology, Campus Bio-Medico University of Rome, via Alvaro del Portillo 200, 00128 Rome, Italy.
Alice
A
Zoccoli
Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy.
Rossana
R
Berardi
School of Pharmacy, Section of Experimental Medicine, University of Camerino, via Madonna delle Carceri 9, 62032 Camerino, Italy.
Giorgio
G
Santoni
Department of Medical Oncology, Campus Bio-Medico University of Rome, via Alvaro del Portillo 200, 00128 Rome, Italy.
Giuseppe
G
Tonini
Department of Medical Oncology, Campus Bio-Medico University of Rome, via Alvaro del Portillo 200, 00128 Rome, Italy.
Daniele
D
Santini
Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy.
Stefano
S
Cascinu
D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C401859:temsirolimus; C546842:MTOR protein, human
Autophagy; Clinical trials; Drug resistance; Mammalian target of rapamycin; Renal cell carcinoma; mTOR inhibitors