The role of TBK1 in cancer pathogenesis and anticancer immunity.
The role of TBK1 in cancer pathogenesis and anticancer immunity.
复制标题
TBK1在肿瘤发病机制和抗癌免疫中的作用。
DOI：
10.1186/s13046-022-02352-y
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发表时间：
2022-04-09
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Runde AP;Mack R;S J PB;Zhang J
TANK结合激酶1（TBK 1）是一种丝氨酸/苏氨酸激酶，属于核因子-κB（IκB）激酶（IKK）家族的非经典抑制剂。TBK 1可被病原体相关分子模式（PAMP）、炎性细胞因子和致癌激酶（包括激活的K-RAS/N-RAS突变体）激活。TBK 1主要介导IRF 3/7活化和NF-κB信号传导，以调节炎性细胞因子的产生和先天免疫的活化。TBK 1还参与调节其他几种细胞活动，包括自噬、线粒体代谢和细胞增殖。虽然TBK 1突变尚未在人类癌症中报道，但异常TBK 1激活与几种类型癌症的肿瘤发生有关，包括白血病和具有KRAS激活突变的实体瘤。因此，TBK 1被认为是这些类型癌症的药理学治疗的可行靶点。研究表明，TBK 1抑制不仅通过直接抑制癌细胞的增殖和存活，而且通过激活抗肿瘤T细胞免疫来抑制癌症发展。已经鉴定和研究了TBK 1的几种小分子抑制剂。然而，到目前为止，只有momelotinib（MMB）/CYT 387在临床试验中被评估为癌症治疗，而amlexanox（AMX）已被临床评估用于治疗II型糖尿病，非酒精性脂肪肝疾病和肥胖症。本文就TBK 1信号通路及其调控机制的研究进展以及TBK 1在肿瘤发病机制中的作用作一综述。我们还讨论了靶向TBK 1用于癌症治疗的潜在分子机制。我们希望我们的努力可以帮助刺激在未来的癌症治疗方法中靶向TBK 1信号传导的新策略的发展。
The TANK-binding kinase 1 (TBK1) is a serine/threonine kinase belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) kinase (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including activated K-RAS/N-RAS mutants. TBK1 primarily mediates IRF3/7 activation and NF-κB signaling to regulate inflammatory cytokine production and the activation of innate immunity. TBK1 is also involved in the regulation of several other cellular activities, including autophagy, mitochondrial metabolism, and cellular proliferation. Although TBK1 mutations have not been reported in human cancers, aberrant TBK1 activation has been implicated in the oncogenesis of several types of cancer, including leukemia and solid tumors with KRAS-activating mutations. As such, TBK1 has been proposed to be a feasible target for pharmacological treatment of these types of cancer. Studies suggest that TBK1 inhibition suppresses cancer development not only by directly suppressing the proliferation and survival of cancer cells but also by activating antitumor T-cell immunity. Several small molecule inhibitors of TBK1 have been identified and interrogated. However, to this point, only momelotinib (MMB)/CYT387 has been evaluated as a cancer therapy in clinical trials, while amlexanox (AMX) has been evaluated clinically for treatment of type II diabetes, nonalcoholic fatty liver disease, and obesity. In this review, we summarize advances in research into TBK1 signaling pathways and regulation, as well as recent studies on TBK1 in cancer pathogenesis. We also discuss the potential molecular mechanisms of targeting TBK1 for cancer treatment. We hope that our effort can help to stimulate the development of novel strategies for targeting TBK1 signaling in future approaches to cancer therapy.
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