Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
Cell Rep. 2018 Sep 25;24(13):3393-3403.e5. doi: 10.1016/j.celrep.2018.08.089.
Cancer cells overexpress a diversity of anti-apoptotic BCL-2 family proteins, such as BCL-2, MCL-1, and BFL-1/A1, to enforce cellular immortality. Thus, intensive drug development efforts have focused on targeting this class of oncogenic proteins to overcome treatment resistance. Whereas a selective BCL-2 inhibitor has been FDA approved and several small molecule inhibitors of MCL-1 have recently entered phase I clinical testing, BFL-1/A1 remains undrugged. Here, we developed a series of stapled peptide design principles to engineer a functionally selective and cell-permeable BFL-1/A1 inhibitor that is specifically cytotoxic to BFL-1/A1-dependent human cancer cells. Because cancers harbor a diversity of resistance mechanisms and typically require multi-agent treatment, we further investigated BFL-1/A1 co-dependencies by mining a genome-scale CRISPR-Cas9 screen. We identified ataxia-telangiectasia-mutated (ATM) kinase as a BFL-1/A1 co-dependency in acute myeloid leukemia (AML), which informed the validation of BFL-1/A1 and ATM inhibitor co-treatment as a synergistic approach to subverting apoptotic resistance in cancer.
癌细胞过度表达多种抗凋亡 BCL-2 家族蛋白，如 BCL-2、MCL-1 和 BFL-1/A1，以维持细胞永生。因此，药物研发的重点集中在靶向这类致癌蛋白，以克服治疗耐药性。虽然一种选择性 BCL-2 抑制剂已获得 FDA 批准，并且几种小分子 MCL-1 抑制剂最近已进入 I 期临床测试，但 BFL-1/A1 仍未被开发。在这里，我们开发了一系列订书肽设计原则，用于设计一种功能选择性和细胞渗透性的 BFL-1/A1 抑制剂，该抑制剂对依赖 BFL-1/A1 的人类癌细胞具有特异性细胞毒性。由于癌症具有多种耐药机制，并且通常需要多药物治疗，我们通过挖掘全基因组 CRISPR-Cas9 筛选进一步研究了 BFL-1/A1 的共依赖性。我们确定共济失调毛细血管扩张突变（ATM）激酶是急性髓细胞白血病（AML）中的 BFL-1/A1 共依赖性，这为验证 BFL-1/A1 和 ATM 抑制剂联合治疗作为一种颠覆癌症凋亡抵抗的协同方法提供了信息。
