Potentiation of Apoptosis in Drug-Resistant Mantle Cell Lymphoma Cells by Mcl-1 Inhibitor Involves Downregulation of Inhibitor of Apoptosis Proteins

Authors

Yijing Li
Heng-Huan Lee
Vivian Changying Jiang
Yuxuan Che
Joseph McIntosh
Alexa Jordan
Jovanny Vargas
Tianci Zhang
Fangfang Yan
Margaret Elizabeth Simmons
Wei Wang
Lei Nie
Yixin Yao
Preetesh Jain
Michael Wang
Yang Liu

Publication Date

11-2-2023

Journal

Cell Death & Disease

Abstract

Bruton's tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have demonstrated tremendous clinical benefits in mantle cell lymphoma (MCL) patients, but intrinsic or acquired resistance inevitably develops. In this study, we assessed the efficacy of the highly potent and selective MCL-1 inhibitor AZD5991 in various therapy-resistant MCL cell models. AZD5991 markedly induced apoptosis in these cells. In addition to liberating BAK from the antiapoptotic MCL-1/BAK complex for the subsequent apoptosis cascade, AZD5991 downregulated inhibitor of apoptosis proteins (IAPs) through a BAK-dependent mechanism to amplify the apoptotic signal. The combination of AZD5991 with venetoclax enhanced apoptosis and reduced mitochondrial oxygen consumption capacity in MCL cell lines irrespective of their BTKi or venetoclax sensitivity. This combination also dramatically inhibited tumor growth and prolonged mouse survival in two aggressive MCL patient-derived xenograft models. Mechanistically, the augmented cell lethality was accompanied by the synergistic suppression of IAPs. Supporting this notion, the IAP antagonist BV6 induced dramatic apoptosis in resistant MCL cells and sensitized the resistant MCL cells to venetoclax. Our study uncovered another unique route for MCL-1 inhibitor to trigger apoptosis, implying that the pro-apoptotic combination of IAP antagonists and apoptosis inducers could be further exploited for MCL patients with multiple therapeutic resistance.

Keywords

Humans, Mice, Animals, Adult, Lymphoma, Mantle-Cell, Myeloid Cell Leukemia Sequence 1 Protein, Inhibitor of Apoptosis Proteins, Down-Regulation, Cell Proliferation, Cell Line, Tumor, Apoptosis, Proto-Oncogene Proteins c-bcl-2

DOI

10.1038/s41419-023-06233-w

PMID

37919300

PMCID

PMC10622549

PubMedCentral® Posted Date

11-2-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes