Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses
Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses
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DOI：
10.20517/cdr.2018.12
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发表时间：
2018-01-01
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影响因子：
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通讯作者：
Heasley, Lynn E.
中科院分区：
文献类型：
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作者：
Gurule, Natalia J.;Heasley, Lynn E.
EGFR、ALK和ROS1中携带致癌突变的受体酪氨酸激酶（RTK）发生在肺腺癌的重要亚组中。靶向依赖于这些致癌RTK的肿瘤细胞的酪氨酸激酶抑制剂（TKI）产生肿瘤缩小，但也产生各种不良事件。皮肤毒性、血液学缺陷、恶心、呕吐、腹泻和头痛是最常见的，更急性且通常致命的副作用如肝衰竭和间质性肺病发生频率较低。在正常上皮中，RTK调节组织稳态。例如，EGFR维持角质形成细胞稳态，而MET调节与组织重塑相关的过程。先前的研究表明，响应EGFR抑制而发生的痤疮样皮疹是由明显的细胞因子和趋化因子释放和不同免疫细胞群的募集驱动的炎症反应的一部分。在机制上，EGFR的阻断引起角质形成细胞内和癌细胞中由该RTK驱动的I型干扰素应答。肿瘤微环境（TME）内的这种先天性免疫应答涉及增加的抗原呈递和效应T细胞募集，其可能参与治疗应答。这种TKI介导的炎症抑制释放代表了一种新的肿瘤细胞脆弱性，可以通过将TKI与依赖于T细胞炎症的免疫肿瘤学药物组合来利用。然而，早期临床数据表明，联合治疗增加了更急性不良事件的频率和程度，特别是肺炎、肝炎和肺纤维化。进一步的临床前研究，以了解TKI介导的炎症和正常上皮细胞，癌细胞和TME之间的串扰是必要的，以改善RTK驱动的癌症患者的治疗方案。
Receptor tyrosine kinases (RTKs) bearing oncogenic mutations in EGFR, ALK and ROS1 occur in a significant subset of lung adenocarcinomas. Tyrosine kinase inhibitors (TKIs) targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage, but also a variety of adverse events. Skin toxicities, hematological deficiencies, nausea, vomiting, diarrhea, and headache are among the most common, with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less frequently. In normal epithelia, RTKs regulate tissue homeostasis. For example, EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling. Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations. Mechanistically, blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this RTK. This innate immune response within the tumor microenvironment (TME) involves increased antigen presentation and effector T cell recruitment that may participate in therapy response. This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for efficacy. However, early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events, especially pneumonitis, hepatitis, and pulmonary fibrosis. Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells, cancer cells, and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.