MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies.
作者： G S Choudhary , S Al-harbi , S Mazumder , B T Hill , M R Smith
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摘要: Overexpression of anti-apoptotic BCL-2 family members is a hallmark many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 rationally designed homology (BH)-3 mimetic specifically binds to BCL-2, but not MCL-1 BCL-xL. Although the thrombocytopenia occurs navitoclax treatment has been problem ABT-199, clinical trials in CLL could benefit by lowering concentration through targeting other survival pathways. In this study, we investigated mechanisms resistance develops therapy generating ABT-199-resistant (ABT199-R) cell lines via exposure NHL ABT-199. Acquired resulted substantial AKT activation upregulation BCL-xL levels sequestered BIM. ABT199-R cells exhibited increased stability failed activate BAX response The acquired inherent resistant were sensitized inhibitors PI3K, AKT, mTOR pathways, NVP-BEZ235 GS-1101. NVP-BEZ235, dual inhibitor p-AKT mTOR, reduced causing BIM release from BCL-xL, thus leading death activation. PI3Kδ GS-1101 (idelalisib) downregulated AKT-mediated A genetic approach, siRNA-mediated down-regulation MCL-1, significantly decreased survival, demonstrating importance these factors for resistance. Our findings suggest novel mechanism modulates expression activity pro-survival proteins confer exploited rational combination therapeutic regimen effective treating malignancies.
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