Abstract 3032: Selective pharmacological activation of the mitochondrial protease OMA1 inhibits tumor growth and induces regression in tumors expressing low levels of FAM210B
Authors: Matthew Kostura, Michael Luther, Michael Stocum, Todd Hembrough, Zahid Bashir
Journal: Cancer Research (2025)

Abstract 1-Thiazol-2-yl-N—3-methyl-1H-pyrozole-5-carboxylic acids have been described as anti-tumor agents. Two members of this family, BTM-3528 and BTM-3566, exhibit robust, single agent in vivo activity in models of Diffuse Large B-Cell Lymphoma (DLBCL). Drug activity is correlated with activation of the OMA1-ATF4 ISR axis. In vitro, response to drug is associated with G1/S growth arrest and , in DLBCL, apoptosis. We evaluated the tumor response activity profile of BTM-3528 and BTM-3566 in vitro in panels of solid and hematopoietic tumor lines. Cell growth inhibition was determined using Cell Titre Glo (Crown Bio OmniScreen). Both compounds demonstrated growth inhibitory activity in a broad range of solid and hematopoietic tumor lines. Biomarker analysis did not reveal correlations between drug activity and mutation or copy number changes associated with tumor oncogenes. Analysis of RNAseq data identified a panel of 9 genes whose expression predicted response to drug. Amongst these is a mitochondrial protein, FAM210B, where response to drug is inversely correlated to RNA expression. We demonstrate that ectopic expression of FAM210B specifically regulates the activity of BTM-3566 but no other compounds that also activate OMA1. BTM-3566 was evaluated in vivo using 16 PDX models of diverse origin including uterine, esophageal and biliary tract (Crown Bio HuBase) . Tumors were prospectively selected based on FAM210B RNA expression (quintile binning). Seven tumors were in the first, lowest quintile, whereas the remaining nine were distributed in the 2nd through 5th quintiles. Response to BTM-3566 occurred exclusively in 5 tumors (uterine, esophageal and biliary tract) within the first quintile of FAM210B expression. Two of the tumors exhibited signs of regression. Selective activation of OMA1 leads to changes in mitochondria including alterations in cristae structure, morphology and expression of BH3 proteins such as MCL1. The outcome is cell growth inhibition and in DLBCL, Bax-dependent apoptosis. Such changes in mitochondrial structure and function may prime tumor cells to apoptosis in the presence of a BH3 mimetic. Combinations of BTM-3566 with the BH3 mimetic navitoclax results in synergistic cell killing activity in select solid tumor lines in vitro. BTM-3566 increased the potency of navitoclax by approximately 7-fold, increasing both cell killing and caspase activation. Conclusions: BTM-3566 targets an pathway important in mitochondrial quality control leading to tumor cell growth and regression. In vivo, drug activity correlated with low expression of RNA for the mitochondrial protein FAM210B. BTM-3566 demonstrated robust activity in vivo in solid tumors of diverse origin with low FAM210B RNA expression. Rational combinations with BH3 mimetics will extend the therapeutic utility of BTM-3566 in otherwise difficult to treat tumors. Citation Format: Matthew Kostura, Michael Luther, Michael Stocum, Todd Hembrough, Zahid Bashir. Selective pharmacological activation of the mitochondrial protease OMA1 inhibits tumor growth and induces regression in tumors expressing low levels of FAM210B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3032.