Constitutive mTOR inhibition in mouse thymic Pre-T LBL identifies Cdk6 as a target for combination treatment of T-ALL/LBL

Authors

• S Zhang
• J Gary
• J Simmons
• J Xu
• B Gamache
• K Zhang
• N Watson
• A Kovalchuk
• A Michalowski
• J Chen
• M Herrmann
• T Thaiwong
• M Kiupel
• W Dubois
• J Testa
• B Mock

Abstract

The PI3K/AKT/mTOR pathway is frequently hyperactivated in T-cell acute lymphoblastic leukemia (T-ALL). To model inhibition of this pathway in lymphoma, mice with T-lymphocyte-specific, constitutively active AKT (Lck-MyrAkt2) were crossed to mice with genetically reduced mTOR expression (knock-down, KD). Mice with genetic reduction of mTOR had increased survival relative to wild type mTOR mice (average survival of 24 versus 14 weeks, respectively), though both developed thymic pre-T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). A similar phenotype was observed when mTOR wild type Lck-MyrAkt2 mice were treated for 8 weeks with the rapamycin analog, everolimus, an inhibitor of the mTOR TORC1 complex. Transcriptional profiling of thymic lymphomas from the mice revealed that mTOR KD was associated with decreased expression of Cdk6, a critical proliferative control node in T-cell development and oncogenic transformation. Pharmacologic inhibition of mTOR in tumor cells also decreased CDK6, suggesting the two proteins have a mechanistic relationship in the tumors. The combination of a mTOR inhibitor (rapamycin) and a CDK4/6 inhibitor (PD-0332991, Palbociclib) synergistically decreased the overall viability and signaling downstream of drug targets in mouse lymphoma cells and in human T-ALL/LBL cell lines. This combination is currently being evaluated in mice using a disseminated leukemia model. Our results suggest that this drug combination inhibiting mTOR and CDK4/CDK6 may be beneficial in the treatment of T-ALL/LBL.

Scientific Focus Area: Molecular Pharmacology

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