Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA; email:
Annu Rev Pharmacol Toxicol. 2018 Jan 6;58:209-229. doi: 10.1146/annurev-pharmtox-010617-052954. Epub 2017 Sep 15.
Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change-often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell-like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.
尽管针对致癌激酶驱动子的靶向抑制在许多癌症中实现了显著的患者应答，但耐药性的发展仍然是一个重大挑战。已经确定了许多机制，包括获得守门突变、激活途径突变，以及驱动子或替代节点的拷贝数损失或增益。这些变化促使开发了选择性更高的激酶抑制剂、使用二线治疗药物来克服原发性耐药性，以及联合治疗来预防耐药性。除了基因组耐药机制外，肿瘤中观察到的适应性转录和信号反应也越来越受到重视，这些改变导致表型状态发生变化——通常表现为上皮-间充质转化或逆转为癌症干细胞样表型，其基础是表观遗传景观的重塑。这种驱动细胞状态变化的表观基因组调节具有多面性，包括抑制和激活组蛋白修饰、DNA 甲基化、增强子重塑和非编码 RNA 种类的调节。因此，将激酶抑制剂与靶向转录机制组件和组蛋白修饰酶的药物联合使用，在临床前和临床研究中显示出了前景。在这里，我们综述了癌症中对激酶抑制的耐药机制，特别强调了重新布线的激酶组和转录信号网络，以及可能被利用来克服这些适应性信号变化的潜在弱点。
