PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

• Published in: The Journal of clinical investigation Vol. 133; no. 13; pp. 1 - 12
• Main Authors: Jayappa, Kallesh D., Tran, Brian, Gordon, Vicki L., Morris, Christopher, Saha, Shekhar, Farrington, Caroline C., O’Connor, Caitlin M., Zawacki, Kaitlin P., Isaac, Krista M., Kester, Mark, Bender, Timothy P., Williams, Michael E., Portell, Craig A., Weber, Michael J., Narla, Goutham
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2023
• Subjects: Animals; Antagonists; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; B cells; BAX protein; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Bcl-x protein; BIM protein; Biomedical research; Cancer; Cancer therapies; Care and treatment; Cell biology; Chronic lymphocytic leukemia; Cytotoxicity; Development and progression; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Multiple; Drug therapy; Genotype & phenotype; Health aspects; Humans; Hypotheses; Immunoprecipitation; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Lymphoma; Lymphomas; Mcl-1 protein; Membrane permeability; Mice; Mitochondrial membranes; Mitochondrial permeability transition pore; Multidrug resistance; Multidrug resistant organisms; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Oncology; Patients; Permeability; Phosphatase; Phosphatases; Phosphoprotein phosphatase; Physiological aspects; Protein phosphatase; Protein Phosphatase 2 - genetics; Proteins; Proto-Oncogene Proteins c-bcl-2; Treatment resistance; Tumor cell lines; Tumorigenesis; United States; Virginia; Oncology; Phosphoprotein phosphatases; Apoptosis pathways; Cancer; Cell Biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI155938

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.