Current status and challenges associated with targeting mTOR for cancer therapy.
The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of PI3K/Akt/mTOR signaling can promote a cellular environment that is favorable for transformation. In fact, dysregulation of this pathway, as a result of genetic mutations and amplifications, is implicated in a variety of human cancers. Therefore, mTOR has emerged as a key target for the treatment of cancer, particularly in the treatment of tumors that exhibit increased mTOR signaling as a result of genetic lesions. The immunosuppressant sirolimus (rapamycin) directly inhibits mTOR activity and suppresses the growth of cancer cells in vitro and in vivo. As a result, a number of sirolimus derivatives have been developed as anti-cancer therapies, and these compounds are currently under investigation in phase I-III clinical trials. In this review, we summarize the use of sirolimus derivatives in clinical trials and address some of the challenges associated with targeting mTOR for the treatment of human cancer.
Dowling
Ryan J O
RJ
Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
Pollak
Michael
M
Sonenberg
Nahum
N
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human