New inhibitors of the mammalian target of rapamycin signaling pathway for cancer.
BACKGROUND
Contrasting with the broad activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) survival pathway in most cancer, activity of rapalogues appears to be restricted to a few tumor types.


METHODS
The analysis of molecular activity of the PI3K/AKT/mTOR pathway and resistance mechanisms of rapamycin and rapalogues led to the development of several inhibitory molecules.


RESULTS
New anticancer agents including PI3K inhibitors, dual PI3K/mTOR inhibitors, specific mTOR inhibitors, and AKT inhibitors may have direct inhibitory effects on targets by competing with ATP or may be non-ATP-competitive allosteric modulators of protein functions. In addition, another way of blocking the abnormal activation of the PI3K/AKT/mTOR pathway may be achieved by using HSP90 inhibitors. In this paper we review novel drugs inhibiting the mTOR signaling pathway.


CONCLUSIONS
Several trials are ongoing with novel drugs targeting key kinases involved in the mTOR pathway. Benchmarking those agents with rapalogues in rationally designed preclinical models and conceiving clinical trials in everolimus/temsirolimus-sensitive tumor types may help to identify drugs with a real clinical potential. Understanding mechanisms associated with primary and acquired resistance to rapalogues may help to enlarge indications and provide a rationale for designing combinations that will minimize the risk of developing resistance to rapalogues.
Albert
Sébastien
S
Service Inter-Hospitalier de Cancérologie Bichat-Beaujon (SIHC), Laboratoire de pharmacobiologie des anticancereux (RayLab), Paris, France.
Serova
Maria
M
Dreyer
Chantal
C
Sablin
Marie-Paule
MP
Faivre
Sandrine
S
Raymond
Eric
E
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C493245:CRTC2 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse