Department of Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Int J Mol Sci. 2021 Jan 14;22(2):792. doi: 10.3390/ijms22020792.
The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.
表皮生长因子受体（EGFRs）的酪氨酸激酶活性在细胞增殖、再生、肿瘤发生和抗癌耐药中发挥着关键作用。对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）有反应并获得生存益处的非小细胞肺癌患者存在体细胞 EGFR 突变。EGFR-TKI 相关不良反应（AEs）通常是可耐受和可管理的，尽管严重的 AEs 包括肺损伤（特别是间质性肺疾病（ILD），导致 58%的 EGFR-TKI 治疗相关死亡）很少发生。EGFR-TKI 诱导的 ILD 的发病机制尚不清楚。风险因素，如吸烟、预先存在的肺纤维化、慢性阻塞性肺疾病和较差的表现状态，表明由于肺损伤的上皮愈合受损，肺炎症情况可能随着 EGFR-TKI 治疗而恶化。在现有文献中，关于 EGFR-TKI 诱导的 ILD 的临床前和临床研究的证据有限。在此，我们评估了 EGFR-TKIs 与 AEs，特别是 ILD 之间的关系。综述了细胞因子丰富环境中诱导肺损伤或耐药性的机制的最新报告。我们讨论了细胞毒性药物或免疫治疗药物与 EGFR-TKIs 联合作为 EGFR-TKI 相关肺损伤潜在机制的相关性，并回顾了有助于从肺损伤中恢复或克服抗 EGFR 治疗耐药性的最新诊断和治疗进展。
