Epigenetic Alterations and Mechanisms That Drive Resistance to Targeted Cancer Therapies.
Epigenetic Alterations and Mechanisms That Drive Resistance to Targeted Cancer Therapies.
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DOI：
10.1158/0008-5472.can-21-1606
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发表时间：
2021-11-15
期刊：
影响因子：
11.2
通讯作者：
Gupta R
中科院分区：
文献类型：
--
作者：
Wajapeyee N;Gupta R
癌症是一种复杂的疾病，癌细胞通常具有多种遗传和表观遗传改变。患者来源的癌症样本的大规模测序已经确定了几个可药物化的驱动癌基因。这些癌基因中的许多可以被靶向以提供针对乳腺癌、白血病、肺癌、黑色素瘤、淋巴瘤和其他癌症类型的有效疗法。对这些药物的初始反应在许多癌症类型中可能是稳健的，并且一些癌症患者经历持续的肿瘤抑制。然而，对这些靶向治疗剂的耐药性经常出现，无论是来自内在的还是后天的机制，对有效治疗构成了主要的临床障碍。已经在不同的癌症类型中确定了几种耐药机制，包括细胞自主和细胞非自主。在这里，我们描述了如何改变的转录组，转录因子，DNA和染色质调节蛋白赋予耐药性的靶向治疗药物。我们还详细介绍了这些研究如何确定驱动耐药性和致癌途径的潜在表观遗传因素，这对耐药癌症的预防和治疗有直接影响。
Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some cancer patients experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell non-autonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.