Reference Detail

Ref Type Journal Article
PMID (18708578)
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
Vol 22
Issue 16
Date 2008 Aug 15
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 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 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 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