TY - JOUR
T1 - The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro
AU - Fatima, Narjis
AU - Shen, Yandong
AU - Crassini, Kyle
AU - Burling, Olivia
AU - Thurgood, Lauren
AU - Iwanowicz, Edwin J.
AU - Lang, Henk
AU - Karanewsky, Donald S.
AU - Christopherson, Richard I.
AU - Mulligan, Stephen P.
AU - Best, O. Giles
PY - 2024
Y1 - 2024
N2 - 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 in vitro 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.
AB - 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 in vitro 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.
KW - Chronic lymphocytic leukemia
KW - ClpP (mitochondrial ATP-dependent Caseinolytic protease P subunit)
KW - imipridone
KW - TR-compounds
KW - tumor microenvironment
KW - venetoclax
UR - http://www.scopus.com/inward/record.url?scp=85182413479&partnerID=8YFLogxK
U2 - 10.1080/10428194.2023.2300055
DO - 10.1080/10428194.2023.2300055
M3 - Article
AN - SCOPUS:85182413479
SN - 1042-8194
VL - 65
SP - 585
EP - 597
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 5
ER -
