Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
Cell Rep. 2021 Mar 16;34(11):108870. doi: 10.1016/j.celrep.2021.108870.
Ibrutinib, a bruton's tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally, and importantly, we find that a robust and facile ex vivo image-based functional drug screening platform can predict clinical therapeutic responses of IR MCL and identify vulnerabilities that can be targeted to disable the evolution of IR.
伊布替尼是一种布鲁顿酪氨酸激酶 (BTK) 抑制剂，在侵袭性套细胞淋巴瘤 (MCL) 中引发了强大的临床反应，但许多患者会复发致死性伊布替尼耐药 (IR) 疾病。在这里，我们使用基因组、化学蛋白质组学和药物筛选分析，报告了增强子重塑介导的转录激活和适应性信号变化驱动了 IR 的侵袭性表型。因此，IR MCL 细胞易受转录机制抑制剂的影响，特别是 cyclin-dependent kinase 9 (CDK9) 抑制剂，CDK9 是 RNA 聚合酶 II (RNAPII) 的正转录延伸因子 b (P-TEFb) 的催化亚基。此外，CDK9 抑制可使重新编程的信号通路失活，并防止 MCL 中出现 IR。最后，也是非常重要的是，我们发现一个强大且简单的基于体外成像的功能药物筛选平台可以预测 IR MCL 的临床治疗反应，并确定可以靶向的脆弱性，以阻止 IR 的进化。
