IRS-1: auditing the effectiveness of mTOR inhibitors.
Rapamycin analogs that inhibit mTOR signaling have antitumor activity against certain lymphomas, but treatment of solid tumors has been less encouraging despite inhibition of mTOR function. Two recent papers give insight into the potential use of mTOR inhibitors. O'Reilly et al. provide evidence that poor tumor response to rapamycins is the result of relieving mTOR-mediated feedback inhibition of insulin receptor substrate 1, and activation of Akt-mediated survival. In the second paper, Kaper et al. address the impact of pathway activation on hypoxia-mediated downregulation of mTOR signaling, raising the possibility that rapalogs could selectively inhibit hypoxic cells.
Easton
John B
JB
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Kurmasheva
Raushan T
RT
Houghton
Peter J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human