Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
O'Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham, Alabama.
Cancer Res. 2021 Nov 15;81(22):5589-5595. doi: 10.1158/0008-5472.CAN-21-1606. Epub 2021 Sep 16.
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 patients with cancer 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 nonautonomous, 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.
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。对患者来源的癌症样本进行大规模测序已经确定了几个可用药的驱动致癌基因。其中许多致癌基因可以通过药理学靶向治疗来为乳腺癌、白血病、肺癌、黑色素瘤、淋巴瘤和其他癌症类型提供有效的治疗方法。这些药物在许多癌症类型中都能产生强大的初始反应，一些癌症患者的肿瘤抑制也能持续。然而，由于内在或获得性机制，这些靶向治疗药物经常会产生耐药性，这对有效治疗构成了重大的临床障碍。在不同的癌症类型中已经确定了几种耐药机制，包括自主和非自主细胞。在这里，我们描述了转录组、转录因子、DNA 和染色质调节蛋白的改变如何赋予对靶向治疗药物的耐药性。我们还详细阐述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，这对预防和治疗耐药性癌症具有直接意义。
