Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cell Rep. 2021 Jan 5;34(1):108532. doi: 10.1016/j.celrep.2020.108532.
Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.
杂臂蛋白水解靶向嵌合体化合物利用 E3 连接酶的活性诱导靶癌蛋白的降解，并表现出强大的临床前抗肿瘤活性。为了解析调节肿瘤细胞对不同类别的蛋白水解药物“降解剂”敏感性的机制，我们进行了基于 CRISPR-Cas9 的全基因组规模基因编辑研究。我们观察到骨髓瘤细胞对不同靶标（BET 溴结构域蛋白、CDK9）降解剂的抗性，并且通过 CRBN（降解基序）或 VHL 发挥作用，主要是通过阻止而不是适应靶癌蛋白的降解来介导的；这涉及到相应的 Cullin-RING 连接酶 (CRL) 复合物的靶 E3 连接酶或相互作用物/调节剂的功能丧失。对基于 CRBN 与基于 VHL 的降解剂的抗性机制的大量基因水平差异从机制上解释了这两种降解剂类别序贯给药时缺乏交叉抗性的原因。利用更多种类的 E3 连接酶/CRL 开发降解剂可能有助于这些药物的序贯/交替与联合使用，从而有可能延迟或预防耐药性的产生。
