RT Journal Article
SR Electronic
T1 Pharmacological activation of the mitochondrial stress protease OMA1 reveals a therapeutic liability in Diffuse Large B-Cell Lymphoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.12.495213
DO 10.1101/2022.06.12.495213
A1 Adrian Schwarzer
A1 Matheus Oliveira
A1 Marc-Jens Kleppa
A1 Scott D. Slattery
A1 Andy Anantha
A1 Alan Cooper
A1 Mark Hannink
A1 Axel Schambach
A1 Anneke Dörrie
A1 Alexey Kotlyarov
A1 Matthias Gaestel
A1 Todd Hembrough
A1 Jedd Levine
A1 Michael Luther
A1 Michael Stocum
A1 Linsey Stiles
A1 Marc Liesa
A1 Matthew J. Kostura
YR 2022
UL http://biorxiv.org/content/early/2022/06/15/2022.06.12.495213.abstract
AB DLBCL are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to adapt to stress caused by uncontrolled growth, such as hypoxia, amino acid deprivation and accumulation of misfolded proteins. Here we show that ISR hyperactivation is a targetable liability in DLBCL. We describe a novel class of compounds represented by BTM-3528 and BTM-3566, that activate the ISR through the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal-center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability which is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell, and MYC-rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. BTM-3566 represents a first- of-its kind approach of selectively hyperactivating the mitochondrial ISR for treating DLBCL.One Sentence Summary Selective pharmacological activation of the mitochondrial integrated stress response promotes therapeutic responses in diffuse large B- cell lymphomaCompeting Interest StatementAdrian Schwarzer: is a member of the Scientific Advisory Board of Bantam Pharmaceutical and received funding in the form of a sponsored research agreement from Bantam Pharmaceuticals. Anneke Dorrie: no conflict of interest Matthias Gaestel: no conflict of interest Marc-Jens Kleppa: no conflict of interest Alexey Kotlyarov: no conflict of interest Axel Schambach: no conflict of interest Marc Liesa: co-founder and consultant of Enspire Bio LLC; received funding in the form of a sponsored research agreement from Bantam Pharmaceuticals. Linsey Stiles: received contract research funding from Bantam Pharmaceuticals. Matheus Pinto: no conflict of interest. Mark Hannink: received funding in the form of a sponsored research agreement from Bantam Pharmaceuticals. Scott Slattery: received contract research funding from Bantam Pharmaceuticals. Andy Anantha: is a paid consultant to Bantam Pharmaceutical. Alan Cooper: is a paid consultant to Bantam Pharmaceutical and is an inventor on patents WO2016196644A1, WO2018102452,WO2018102453, WO2020243582-PAMPH-20201203-0751-1, WO2020243584-PAMPH-20201203-0103 associated with the information in this paper Todd Hembrough: is a paid consultant to Bantam Pharmaceutical. Matthew Kostura: is a paid consultant to Bantam Pharmaceutical and is an inventor on patents WO2018102452,WO2018102453 and patent application WO/2019/236936 associated with the information in this paper. Jedd Levine: is a paid consultant to Bantam Pharmaceutical and is an inventor on patents and is an inventor on patents WO2018102452 and WO2018102453 associated with the information in this paper. Michael Luther: is an employee of Bantam Pharmaceutical and is an inventor on patents WO2018102452, WO2018102453 and patent application WO/2019/236936 associated with the information in this paper. Michael Stocum: is an employee of Bantam Pharmaceutical.