Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Mahesh Tambe, Sarah Unterberger, Mette C Kriegbaum, Ida Vänttinen, Ezgi June Olgac, Markus Vähä-Koskela, Mika Kontro, Krister Wennerberg, Caroline A Heckman
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Abstract

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.

Venetoclax 在耐 Venetoclax 的急性髓性白血病细胞中引发亚致死性凋亡信号,并诱导细胞易受 PARP 抑制和阿扎胞苷的影响。
Venetoclax 加阿扎胞苷治疗对老年和体质不佳的急性髓性白血病(AML)患者有临床疗效。然而,该疗法很少能治愈疾病,最终会出现因耐药而复发的情况。由于目前临床上尚无对获得性venetoclax耐药有效的治疗方法,这已成为急性髓性白血病治疗中的一大挑战。在研究对 venetoclax 产生耐药性的 AML 细胞系时,我们观察到,尽管细胞的存活和生长未受影响,但 venetoclax 会诱导亚致死性细胞凋亡信号传导和 DNA 损伤。这种效应可能是由于 Venetoclax 诱导了亚致死程度的线粒体外膜通透。基于这些结果,我们推测,venetoclax 诱导的亚致死性凋亡信号转导可能是耐venetoclax 的 AML 细胞的一个弱点。这一点得到了多种药物筛选的支持,我们观察到 venetoclax 和 PARP 抑制剂对 venetoclax 耐药细胞有协同作用。此外,venetoclax-PARP 抑制剂组合还能防止治疗幼稚的 AML 细胞系产生 venetoclax 耐药性。此外,在 Venetoclax-PARP 抑制剂组合中加入阿扎胞苷,可增强 Venetoclax 诱导的 DNA 损伤,并在 Venetoclax 耐药的 AML 细胞系和接受 Venetoclax-azacitidine 治疗后临床复发的 AML 患者样本中显示出卓越的敏感性和长期反应。总之,我们从机理上确定了获得性 Venetoclax 耐药 AML 细胞的新弱点,并将 PARP 抑制确定为克服 AML 获得性 Venetoclax 耐药的潜在治疗方法。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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