Oncotarget

Research Papers:

Preferential targeting of MCL-1 by a hydrocarbon-stapled BIM BH3 peptide

Abbas Hadji, Greta K. Schmitt, Mathew R. Schnorenberg, Lauren Roach, Connie M. Hickey, Logan B. Leak, Matthew V. Tirrell and James L. LaBelle _

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Oncotarget. 2019; 10:6219-6233. https://doi.org/10.18632/oncotarget.27262

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Abstract

Abbas Hadji1, Greta K. Schmitt1, Mathew R. Schnorenberg1,2, Lauren Roach1, Connie M. Hickey1, Logan B. Leak1, Matthew V. Tirrell2 and James L. LaBelle1

1 Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation and Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA

2 Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA

Correspondence to:

James L. LaBelle,email: jlabelle@peds.bsd.uchicago.edu

Keywords: MCL-1; BIM; BH3 mimetic; stapled peptides; apoptosis

Received: February 08, 2019     Accepted: October 04, 2019     Published: October 22, 2019

ABSTRACT

BCL-2 family proteins are central regulators of apoptosis and represent prime therapeutic targets for overcoming cell death resistance in malignancies. However, plasticity of anti-apoptotic members, such as MCL-1, often allows for a switch in cell death dependency patterns that lie outside the binding profile of targeted BH3-mimetics. Therefore discovery of therapeutics that effectively inactivate all anti-apoptotic members is a high priority. To address this we tested the potency of a hydrocarbon stapled BIM BH3 peptide (BIM SAHBA) to overcome both BCL-2 and MCL-1 apoptotic resistance given BIM’s naturally wide ranging affinity for all BCL-2 family multidomain members. BIM SAHBA effectively killed diffuse large B-cell lymphoma (DLBCL) cell lines regardless of their anti-apoptotic dependence. Despite BIM BH3’s ability to bind all BCL-2 anti-apoptotic proteins, BIM SAHBA’s dominant intracellular target was MCL-1 and this specificity was exploited in sequenced combination BH3-mimetic treatments targeting BCL-2, BCL-XL, and BCL-W. Extending this MCL-1 functional dependence, mouse embryonic fibroblasts (MEFs) deficient in MCL-1 were resistant to mitochondrial changes induced by BIM SAHBA. This study demonstrates the importance of understanding BH3 mimetic functional intracellular affinities for optimized use and highlights the diagnostic and therapeutic promise of a BIM BH3 peptide mimetic as a potential MCL-1 inhibitor.


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