Bollino Dominique, Ma Xinrong, Tighe Kayla M, Casildo Andrea, Richard Katharina, Passaniti Antonino, Carter-Cooper Brandon, Strovel Erin T, Emadi Ashkan
Department of Medical Oncology, Cancer Institute, West Virginia University, Morgantown, WV 26506, USA.
Department of Medical Oncology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA.
Int J Mol Sci. 2024 Dec 5;25(23):13091. doi: 10.3390/ijms252313091.
Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of -derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting asparaginase calaspargase pegol-mknl (CalPegA). We report that CalPegA enhances the anti-leukemic effect of S55746 but does not impact the activity of S63845. The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML.
我们之前的研究表明，长效天冬酰胺酶聚乙二醇化crisantaspase（PegC）在体外和体内均能与BCL-2抑制剂维奈克拉（Ven）协同作用；然而，源自天冬酰胺酶与BCL-2抑制联合使用的抗白血病活性，以及与MCL-1抑制剂（BCL-2抑制的关键耐药因子）的潜在协同作用，尚未得到确定。通过结合使用人急性髓系白血病（AML）细胞系、原代样本和体内异种移植小鼠模型，我们确定了BCL-2抑制剂S55746和MCL-1抑制剂S63845单独使用以及与长效天冬酰胺酶聚乙二醇化卡拉天冬酰胺酶（CalPegA）联合使用时的抗白血病活性。我们报告称，CalPegA增强了S55746的抗白血病作用，但不影响S63845的活性。S55746与CalPegA的联合用药抑制了蛋白质合成，并增加了eIF4E/4EBP1的相互作用，这表明其抑制了翻译复合物的形成。这些结果支持对CalPegA与BCL-2抑制联合用于AML进行临床评估。
