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|Ref Type||Journal Article|
|Authors||Mavrakis KJ, Zhu H, Silva RL, Mills JR, Teruya-Feldstein J, Lowe SW, Tam W, Pelletier J, Wendel HG|
|Title||Tumorigenic activity and therapeutic inhibition of Rheb GTPase.|
|Journal||Genes & development|
|Date||2008 Aug 15|
|Abstract Text||The AKT-mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug's anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|AKT1 act mut||lymphoma||decreased response||Doxorubicin||Preclinical - Cell line xenograft||Actionable||In a preclinical study, lymphoma cells overexpressing constitutively active Akt demonstrated reduced sensitivity to Adriamycin (doxorubicin) treatment in cell line xenograft models (PMID: 18708578).||18708578|
|AKT1 act mut||lymphoma||predicted - sensitive||Doxorubicin + Sirolimus||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Rapamune (sirolimus) and Adriamycin (doxorubicin) combination treatment resulted in improved survival and prolonged remission in cell line xenograft animal models of lymphoma overexpressing constitutively active Akt (PMID: 18708578).||18708578|
|AKT1 act mut||lymphoma||no benefit||Sirolimus||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Rapamune (sirolimus) treatment did not improve survival in cell line xenograft animal models of lymphoma overexpressing constitutively active Akt (PMID: 18708578).||18708578|