title: Overcoming resistance to rapalogs in gliomas by combinatory therapies.
abstract: Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. michal.grzmil@fmi.ch
authors: Michal
authors: M
authors: Grzmil
authors: Brian A
authors: BA
authors: Hemmings
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus