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|Ref Type||Journal Article|
|Authors||Ezell SA, Wang S, Bihani T, Lai Z, Grosskurth SE, Tepsuporn S, Davies BR, Huszar D, Byth KF|
|Title||Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma.|
|Date||2016 Feb 23|
|Abstract Text||Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL.|
|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|
|Unknown unknown||diffuse large B-cell lymphoma||not applicable||AT-7867||Preclinical - Cell culture||Actionable||In a preclinical study, AT-7867 inhibited the growth of diffuse large B-cell lymphoma cell lines in culture (PMID: 26824321).||26824321|