Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Camperdown, Australia.
School of Life and Environmental Sciences, University of Sydney, Camperdown, Australia.
Leuk Lymphoma. 2024 May;65(5):585-597. doi: 10.1080/10428194.2023.2300055. Epub 2024 Jan 16.
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.
尽管在治疗方面取得了进展，但相当一部分慢性淋巴细胞白血病 (CLL) 患者会因耐药性疾病而复发。Imipridones、ONC-201 和 ONC-212 对多种不同的癌症有效，包括急性髓性白血病 (AML) 和脑、乳房和前列腺的肿瘤。这些药物通过激活线粒体蛋白酶、组织蛋白酶 (CIpP) 和未折叠蛋白反应 (UPR) 诱导细胞死亡。在这里，我们证明了新型 imipridone 类似物 TR-57 在模拟肿瘤微环境的条件下作为单一药物对 CLL 细胞具有疗效，并与 venetoclax 协同作用。蛋白质表达的变化表明 TR-57 激活 UPR，抑制 AKT 和 ERK1/2 途径，并诱导 BCL-2 家族蛋白表达的促凋亡变化。该研究表明，TR-57 作为单一药物和与 venetoclax 联合使用，可能是 CLL 的一种有效治疗选择。
