Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Neoplasia. 2024 Nov;57:101046. doi: 10.1016/j.neo.2024.101046. Epub 2024 Sep 5.
The bromodomain and extraterminal (BET) family of proteins show altered expression across various cancers. The members of the bromodomain (BRD) family contain epigenetic reader domains that bind to acetylated lysine residues in both histone and non-histone proteins. Since BRD proteins are involved in cancer initiation and progression, therapeutic targeting of these proteins has recently been an area of interest. In experimental settings, JQ1, a commonly used BRD inhibitor, is the first known inhibitor to target BRD-containing protein 4 (BRD4), a ubiquitously expressed BRD and extraterminal family protein. BRD4 is necessary for a normal cell cycle, and its aberrant expression activates pro-inflammatory cytokines, leading to tumor initiation and progression. Various BRD4 inhibitors have been developed recently and tested in preclinical settings and are now in clinical trials. However, as with many targeted therapies, BRD inhibitor treatment can lead to resistance to treatment. Here, we investigated the kinases up-regulated on JQ1 treatment that may serve as target for combination therapy along with BRD inhibitors. To identify kinase targets, we performed a comparative analysis of gene expression data using RNA from BRD inhibitor-treated cells or BRD-modulated cells and identified overexpression of several kinases, including FYN, NEK9, and ADCK5. We further validated, by immunoblotting, the overexpression of FYN tyrosine kinase; NEK9 serine/threonine kinase and ADCK5, an atypical kinase, to confirm their overexpression after BRD inhibitor treatment. Importantly, our studies show that targeting FYN or NEK9 along with BRD inhibitor effectively reduces proliferation of cancer cells. Therefore, our research emphasizes a potential approach of utilizing inhibitors targeting some of the overexpressed kinases in conjunction with BRD inhibitors to enhance therapeutic effectiveness.
溴结构域和末端（BET）家族的蛋白质在各种癌症中表现出改变的表达。溴结构域（BRD）家族的成员包含表观遗传读取结构域，这些结构域与组蛋白和非组蛋白蛋白质中的乙酰化赖氨酸残基结合。由于 BRD 蛋白参与癌症的起始和进展，因此最近针对这些蛋白的治疗靶向已成为一个研究领域。在实验环境中，JQ1，一种常用的 BRD 抑制剂，是第一个已知的靶向包含 BRD 的蛋白 4（BRD4）的抑制剂，BRD4 是一种广泛表达的 BRD 和末端家族蛋白。BRD4 是正常细胞周期所必需的，其异常表达激活促炎细胞因子，导致肿瘤起始和进展。最近已经开发了各种 BRD4 抑制剂，并在临床前环境中进行了测试，现在正在进行临床试验。然而，与许多靶向治疗一样，BRD 抑制剂治疗可能导致对治疗的耐药性。在这里，我们研究了在 JQ1 处理时上调的激酶，这些激酶可能作为与 BRD 抑制剂联合治疗的靶标。为了鉴定激酶靶标，我们使用来自 BRD 抑制剂处理的细胞或 BRD 调节的细胞的 RNA 进行了基因表达数据的比较分析，并鉴定了几种激酶的过表达，包括 FYN、NEK9 和 ADCK5。我们通过免疫印迹进一步验证了 FYN 酪氨酸激酶的过表达；NEK9 丝氨酸/苏氨酸激酶和 ADCK5，一种非典型激酶，以确认它们在 BRD 抑制剂处理后过表达。重要的是，我们的研究表明，靶向 FYN 或 NEK9 以及 BRD 抑制剂可有效降低癌细胞的增殖。因此，我们的研究强调了一种潜在的方法，即利用针对一些过表达激酶的抑制剂与 BRD 抑制剂联合使用，以提高治疗效果。
