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

• Published in: Cell death & disease Vol. 6; no. 1; p. e1593
• Main Authors: Choudhary, G S, Al-harbi, S, Mazumder, S, Hill, B T, Smith, M R, Bodo, J, Hsi, E D, Almasan, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/2; 13/31; 38/90; 631/61/2049; 631/80/86; 692/699/67/1059/2326; 692/699/67/1990/291/1621/1915; 82/1; 96/106; AKT protein; Antibodies; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Bcl-2-Like Protein 11; Bcl-x protein; bcl-X Protein - genetics; bcl-X Protein - metabolism; BIM protein; Biochemistry; Biomedical and Life Sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell activation; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Cell survival; Chronic exposure; Chronic lymphocytic leukemia; Clinical trials; Down-regulation; Down-Regulation - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; Homology; Humans; Imidazoles - pharmacology; Immunology; Life Sciences; Lymphoma - enzymology; Lymphoma - genetics; Lymphoma - pathology; Malignancy; Mcl-1 protein; Membrane Proteins - metabolism; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Non-Hodgkin's lymphoma; Original; original-article; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Protein Stability - drug effects; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Purines - pharmacology; Quinazolinones - pharmacology; Quinolines - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; siRNA; Sulfonamides - pharmacology; Thrombocytopenia; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Up-Regulation - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.525

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