Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
University of Science and Technology of China, Hefei, 230026, China.
Cell Death Dis. 2021 Aug 12;12(8):789. doi: 10.1038/s41419-021-04073-0.
We previously found that preformed complexes of BAK with antiapoptotic BCL2 proteins predict BH3 mimetic sensitivities in lymphohematopoietic cells. These complexes have not previously been examined in solid tumors or in the context of conventional anticancer drugs. Here we show the relative amount of BAK found in preformed complexes with MCL1 or BCLX varies across ovarian cancer cell lines and patient-derived xenografts (PDXs). Cells bearing BAK/MCL1 complexes were more sensitive to paclitaxel and the MCL1 antagonist S63845. Likewise, PDX models with BAK/MCL1 complexes were more likely to respond to paclitaxel. Mechanistically, BIM induced by low paclitaxel concentrations interacted preferentially with MCL1 and displaced MCL1-bound BAK. Further studies indicated that cells with preformed BAK/MCL1 complexes were sensitive to the paclitaxel/S63845 combination, while cells without BAK/MCL1 complexes were not. Our study suggested that the assessment of BAK/MCL1 complexes might be useful for predicting response to paclitaxel alone or in combination with BH3 mimetics.
我们之前发现，BAK 与抗凋亡 BCL2 蛋白形成的预形成复合物可预测淋巴造血细胞中 BH3 模拟物的敏感性。这些复合物以前尚未在实体瘤或常规抗癌药物的背景下进行过检查。在这里，我们显示在卵巢癌细胞系和患者来源的异种移植（PDX）中，与 MCL1 或 BCLX 形成的预形成复合物中发现的 BAK 的相对量有所不同。携带 BAK/MCL1 复合物的细胞对紫杉醇和 MCL1 拮抗剂 S63845 更敏感。同样，具有 BAK/MCL1 复合物的 PDX 模型更有可能对紫杉醇产生反应。从机制上讲，低紫杉醇浓度诱导的 BIM 优先与 MCL1 相互作用，并取代 MCL1 结合的 BAK。进一步的研究表明，具有预形成的 BAK/MCL1 复合物的细胞对紫杉醇/S63845 联合用药敏感，而没有 BAK/MCL1 复合物的细胞则不敏感。我们的研究表明，评估 BAK/MCL1 复合物可能有助于预测紫杉醇单独或与 BH3 模拟物联合治疗的反应。
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