PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis
Kallesh D. Jayappa, … , Michael J. Weber, Goutham Narla
Kallesh D. Jayappa, … , Michael J. Weber, Goutham Narla
Published May 11, 2023
Citation Information: J Clin Invest. 2023;133(13):e155938. https://doi.org/10.1172/JCI155938.
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Research Article Cell biology Oncology

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

Abstract

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.

Authors

Kallesh D. Jayappa, Brian Tran, Vicki L. Gordon, Christopher Morris, Shekhar Saha, Caroline C. Farrington, Caitlin M. O’Connor, Kaitlin P. Zawacki, Krista M. Isaac, Mark Kester, Timothy P. Bender, Michael E. Williams, Craig A. Portell, Michael J. Weber, Goutham Narla

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Figure 6

DT-061 overcomes antiapoptotic multidrug resistance in CLL xenograft mouse model in vivo.

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DT-061 overcomes antiapoptotic multidrug resistance in CLL xenograft mou...
(A) Tumor growth in mice subcutaneously inoculated with the WT MEC1 cell line and treated with vehicle, DT-061, or the combination of IBR and VEN as indicated. (B) Tumor growth in mice inoculated with Bax/Bak-DKO MEC1 cells and treated with vehicle, DT-061, or the combination of IBR and VEN. (C and D) Percentage of body weight change during drug treatment in mice inoculated with WT (C) or Bax/Bak-DKO (D) MEC1 cells. Data are presented as the mean ± SEM. Statistical significance was determined by 2-way ANOVA with Dunnet’s post hoc test for multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.