Repressing DNA repair to enhance chemotherapy: targeting MyD88 in colon cancer.
Repressing DNA repair to enhance chemotherapy: targeting MyD88 in colon cancer.
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DOI：
10.1093/jnci/djt148
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发表时间：
2013-07
期刊：
影响因子：
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通讯作者：
E. Williamson;R. Hromas
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文献类型：
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作者：
E. Williamson;R. Hromas
细胞分裂得越多，其 DNA 就越不稳定，复制过程中遭受的 DNA 损伤也就越多。因此，细胞通常需要 DNA 修复才能完成 DNA 复制周期。癌细胞对 DNA 修复的这种要求特别敏感，因为它们在复制 DNA 时不受正常细胞的大多数控制。因此，癌细胞破坏 DNA 修复途径以维持复制，并防止有丝分裂灾难引起的细胞凋亡 [在 (1) 中进行了综述]。这种 DNA 修复的增强被癌症治疗进一步选择，并且通常会导致耐药性。矛盾的是，许多癌症在 DNA 修复方面存在缺陷，导致其最初的基因组不稳定并首先转化为恶性肿瘤。癌细胞通过越来越依赖（实际上是沉迷于）替代 DNA 修复途径进行复制来解决这一悖论 (1)。针对这些替代 DNA 修复途径不仅会导致增殖减少，还会导致复制过程中 DNA 从头损伤增加，最终导致细胞凋亡。这种 DNA 修复靶向是合成致死的一种形式，是过去十年中最有前途的药物开发概念之一 (1)。在对经典细胞毒性化疗反应较差的恶性肿瘤（例如结肠癌）中，综合致死率尤其令人感兴趣。在本期杂志中，Kfoury 及其同事证明 MyD88 是结肠癌合成致死的新靶点 (2)。他们发现，在不暴露于任何外部因素的情况下，抑制 MyD88 会导致复制过程中的从头 DNA 损伤，并且这种增加的损伤会产生更多的细胞凋亡 (2)。这项工作背后的假设很有趣：许多研究表明，患有炎症性肠病（例如溃疡性结肠炎和克罗恩病）的个体患结肠癌的风险增加 (3,4)。这种肠道粘膜炎症反应是由 Toll 样受体 (TLR) 和白细胞介素 1 受体 (IL-1R) 引发的信号级联介导的。这种炎症信号级联在结肠粘膜细胞中的持续存在可能是炎症性肠病患者发生癌症的关键 (5)。然而，持续性炎症体信号传导导致肿瘤转化的机制尚未得到很好的描述 (5)。此前，Renno、Kfoury 和该小组的同事发现 MyD88 充当 TLR/IL-1R 炎症信号传导通路与 Ras 致癌信号传导通路之间的桥梁 (6)。 TLR/IL-1R 的激活导致 MyD88 激活 Ras 及其效应器 ERK。已知 MyD88 是 Ras 依赖性信号传导和转化所必需的 (6)。其他研究发现 MyD88 的表达在几种类型的恶性肿瘤中增加 (7,8)。克福里等人。此处报告称，抑制 MyD88 表达可减少结肠癌细胞系和鼠异种移植结肠癌的增殖、增加细胞凋亡并增加对 DNA 交联剂顺铂的敏感性 (2)。这些研究表明，MyD88 抑制可在结肠癌细胞中产生综合致死作用，而结肠癌细胞通常依赖 Ras 来提供增殖信号 (2,6)。克福里等人。他们在具有激活 Ras 突变的结肠癌细胞系中进行了实验。在这些结肠癌细胞系中，MyD88 蛋白的减少导致 p53 及其靶标 p21 的表达增加，表明 p53 通路响应 MyD88 的减少而被激活。当在 p53 缺陷的细胞中重复这些实验时，MyD88 沉默后没有观察到细胞凋亡，这表明功能性 p53 是启动细胞凋亡所必需的。 DNA 从头损伤的增加以及细胞凋亡是如何介导的？ Ras 途径促进 ERCC1 转录增加，ERCC1 是核苷酸切除修复机制的重要组成部分 (9,10)。 Kfoury 及其同事发现，与 MyD88 增强 Ras 激活一致，抑制 MyD88 确实会减少 ERCC1 表达，从而导致复制造成的 DNA 损伤增加。添加回强制表达 ERCC1 的载体，可将 DNA 从头复制损伤降至正常水平。尽管很有趣，但这些体外观察结果需要通过体内研究来证实是否具有临床意义。为此，Kfoury 等人。工程化结肠癌细胞系具有多西环素诱导的 MyD88 抑制，并将这些细胞植入裸鼠皮下。在这个异种移植系统中，MyD88缺陷型肿瘤比表达MyD88的对照肿瘤小5倍，并且从头凋亡增加。重要的是，MyD88 缺陷的肿瘤对顺铂也更敏感，可能是因为 Ras 介导的 ERCC1 表达减少。 ERCC1 是核苷酸切除 DNA 修复机制的重要组成部分，该系统有助于去除顺铂 DNA 加合物 (11)。有报道称，ERCC1 的低表达是一个良好的预后指标，这意味着它可能是一个治疗靶点 (12,13)。克福里等人。进一步证明 MyD88 对顺铂敏感性的影响是由 ERCC1 介导的，表明 MyD88 沉默不会增加细胞对依托泊苷（拓扑异构酶 II 抑制剂）或紫杉醇（微管蛋白干扰剂）的敏感性。对这些药物的耐药性不需要 ERCC1 或 NER 途径 (14,15)。人们可能会认为 MyD88 对奥沙利铂（一种比顺铂更常用于治疗结肠癌的药物）具有相同的作用，并且抑制 MyD88 也会增加对奥沙利铂的敏感性。这些发现在两个层面上具有生物学意义。首先，他们深入了解慢性炎症信号传导如何导致结肠肿瘤转化。这些研究将炎性体信号转导与 MyD88 的 Ras 激活联系起来，Ras 激活是结肠肿瘤发生的已知驱动因素。由于 Ras 已被证明难以瞄准，因此破坏 Ras 之上的上游步骤（例如 MyD88）可能会更有效。也许 MyD88 抑制可能会降低具有持续 TLR/IL-1R 激活的结肠粘膜的转化率。其次，这项工作将 MyD88/Ras 信号传导定义为通过增强 ERCC1 表达来抵抗 DNA 交联化疗的介质。在结肠癌治疗过程中，靶向 MyD88 而不是 ERCC1 特别有吸引力，因为它还可能通过减少 ERCC1 上游的 Ras 激活来减缓增殖速率。因此，这项工作将 MyD88 定义为结肠癌中新型且具有临床意义的合成致死靶点。
The more a cell divides, the more unstable its DNA is and the more DNA damage it sustains during replication. Thus, cells often require DNA repair to simply progress through a DNA replication cycle. Cancer cells are especially sensitive to this requirement for DNA repair because they replicate their DNA without most of the controls normal cells have. Thus, cancer cells subvert DNA repair pathways to maintain replication, and prevent apoptosis from mitotic catastrophe [reviewed in (1)]. This enhancement of DNA repair is further selected for by cancer therapy and commonly leads to resistance. The paradox of this is that many cancers have defects in DNA repair that lead to their original genomic instability and transformation to malignancy in the first place. Cancer cells resolve this paradox by becoming increasingly reliant on, indeed addicted to, alternative DNA repair pathways for replication (1). Targeting these alternative DNA repair pathways can lead to not only decreases in proliferation but also increases in de novo DNA lesions during replication and ultimately apoptosis. Such targeting of DNA repair is one form of synthetic lethality, which is one of the most promising drug development concepts in the last decade (1). Synthetic lethality is especially intriguing in malignancies that are less responsive to classic cytotoxic chemotherapy, such as colon cancer. In this issue of the Journal, Kfoury and colleagues demonstrated that MyD88 is a novel target for synthetic lethality in colon cancer (2). They found that repressing MyD88 induced de novo DNA damage from replication alone without exposure to any external agent and this increased damage produced more apoptosis (2). The hypothesis behind this work is intriguing: Many studies have shown that individuals with inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease, have an increased risk of colon cancer (3,4). This gut mucosal inflammatory response is mediated by signaling cascades initiated from Toll-like receptors (TLRs) and the interleukin 1 receptor (IL-1R). Persistence of this inflammatory signaling cascade in the colonic mucosal cell may be the key to the development of cancer in inflammatory bowel disease patients (5). However, the mechanism by which persistent inflammasome signaling results in neoplastic transformation has not been well described (5). Previously Renno, Kfoury, and colleagues in this group found that MyD88 acts as a bridge between the inflammatory signaling pathways from the TLR/IL-1R and the Ras oncogenic signaling pathway (6). Activation of TLR/IL-1R led to activation of Ras, and its effector ERK, by MyD88. MyD88 is known to be required for Ras-dependent signaling and transformation (6). Other studies found that expression of MyD88 is increased in several types of malignancies (7,8). Kfoury et al. report here that inhibiting MyD88 expression reduced colon cancer cell line and murine xenograft colon cancer proliferation, increased apoptosis, and increased sensitivity to the DNA cross-linker cisplatin (2). These studies demonstrate that MyD88 inhibition produces synthetic lethality in colon cancer cells, which often rely on Ras for proliferative signals (2,6). Kfoury et al. performed their experiments in colon cancer cell lines with activating Ras mutations. In these colon cancer cell lines, a decrease in MyD88 protein produced an increase in the expression of both p53 and its target p21, indicating that the p53 pathway was activated in response to MyD88 reduction. When these experiments were repeated in cells deficient in p53, no apoptosis was observed upon MyD88 silencing, demonstrating that functional p53 was required for initiation of apoptosis. How is the increase in de novo DNA damage, and therefore apoptosis, being mediated? The Ras pathway promotes increased transcription of ERCC1, an essential component of the nucleotide excision repair machinery (9,10). Consistent with MyD88 enhancing Ras activation, Kfoury and colleagues found that indeed repressing MyD88 reduced ERCC1 expression, which resulted in increased DNA damage from replication. Adding back a vector that forced expression of ERCC1 reduced the de novo replicative DNA damage back down to normal levels. Although interesting, these in vitro observations needed to be confirmed by in vivo studies to have any clinical relevance. For this, Kfoury et al. engineered colon cancer cell lines to have doxycycline-inducible repression of MyD88 and implanted these cells subcutaneously in nude mice. In this xenograft system, the MyD88-deficient tumors were 5 times smaller than the control MyD88-expressing tumors and had increased de novo apoptosis. Importantly, the MyD88-deficient tumors were also more sensitive to cisplatin, probably because of the decrease in Ras-mediated expression of ERCC1. ERCC1 is an essential component of the nucleotide excision DNA repair machinery, a system that assists in removing cisplatin DNA adducts (11). There are reports that low expression of ERCC1 is a good prognostic indicator, implying that it might be a therapeutic target (12,13). Kfoury et al. provided further evidence that this effect of MyD88 on cisplatin sensitivity is mediated by ERCC1 by showing that MyD88 silencing did not increase the sensitivity of the cells to etoposide (a topoisomerase II inhibitor) or paclitaxel (a tubulin-disrupting agent). Resistance to these agents does not require ERCC1 or the NER pathway (14,15). One would assume that MyD88 would have the same effect on oxaliplatin, a drug more commonly used for colon cancer than cisplatin, and that repressing MyD88 would also increase sensitivity to oxaliplatin. These findings are biologically significant on two levels. First, they provide insight into how chronic inflammatory signaling might generate colonic neoplastic transformation. These studies link inflammasome signaling to Ras activation, a known driver of colonic oncogenesis, by MyD88. Because Ras has proven difficult to target, perhaps disrupting an upstream step above Ras, such as MyD88, might prove more effective. Perhaps MyD88 inhibition might decrease transformation rates in colonic mucosa harboring constant TLR/IL-1R activation. Second, this work defines MyD88/Ras signaling as a mediator of resistance to DNA cross-linking chemotherapy by enhanced expression of ERCC1. Targeting MyD88 as opposed to ERCC1 during colon cancer therapy is especially attractive because it might also slow proliferative rates by reducing Ras activation upstream of ERCC1. Thus, this work defines MyD88 as a novel and clinically significant synthetic lethal target in colon cancer.