The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro

• Published in: Leukemia & lymphoma Vol. 65; no. 5; p. 585
• Main Authors: Fatima, Narjis, Shen, Yandong, Crassini, Kyle, Burling, Olivia, Thurgood, Lauren, Iwanowicz, Edwin J, Lang, Henk, Karanewsky, Donald S, Christopherson, Richard I, Mulligan, Stephen P, Best, O Giles
• Format: Journal Article
• Language: English
• Published: United States 01.05.2024
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cell Line, Tumor; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction - drug effects; Sulfonamides - pharmacology; Unfolded Protein Response - drug effects; Chronic lymphocytic leukemia; ClpP (mitochondrial ATP-dependent Caseinolytic protease P subunit); imipridone; tumor microenvironment; venetoclax; TR-compounds
• ISSN: 1029-2403
• DOI: 10.1080/10428194.2023.2300055

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.