A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers
James L. LaBelle, … , Andrew L. Kung, Loren D. Walensky
James L. LaBelle, … , Andrew L. Kung, Loren D. Walensky
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):2018-2031. https://doi.org/10.1172/JCI46231.
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Research Article

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

Abstract

Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2–interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence–specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death.

Authors

James L. LaBelle, Samuel G. Katz, Gregory H. Bird, Evripidis Gavathiotis, Michelle L. Stewart, Chelsea Lawrence, Jill K. Fisher, Marina Godes, Kenneth Pitter, Andrew L. Kung, Loren D. Walensky

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Figure 8

Pharmacologic replacement of BIM BH3 restores the death pathway in Bim–/– immune cell infiltrates.

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Pharmacologic replacement of BIM BH3 restores the death pathway in Bim–/...
(A) The infiltrative B cell disease of Bim–/– mice was recapitulated in irradiated Rag2–/–gc–/– mice transplanted with the bone marrow of Bim–/– mice. Histologic analysis by H&E stain and anti-B220 immunohistochemistry at 19 weeks post transplant revealed extensive B cell infiltration of solid organs. Original magnification: ×2 (whole organs); ×40 (H&E), ×20 (B220 immunohistochemistry). (B and C) Increased TUNEL staining was evident in the aberrant infiltrates of BIM SAHBA–treated mice as compared with that in vehicle- and BIM SAHBA(R153D)–treated animals. Importantly, the observed increase in TUNEL positivity in BIM SAHBA–treated mice appeared restricted to the deregulated B cells and was not evident in the normal parenchymal tissue. Original magnification, ×100. (D) The percentage TUNEL positivity within the immune cell infiltrates was calculated by counting approximately 6,000 cells per 5-μm tissue section from each experimental animal (n = 4 per cohort) in a blinded fashion. A statistically significant increase in percentage of TUNEL positivity was observed in the kidney (P = 0.007) and liver (P = 0.0007) infiltrates of BIM SAHBA–treated mice, an effect that was abrogated by R153D point mutagenesis. Data are mean ± SD. **P < 0.01. (E) Importantly, no increase in the number of TUNEL-positive cells was found in kidney and liver parenchymal tissue devoid of the infiltrates. Data are mean ± SD.