Antitumor Efficacy of EGFR-Targeted Recombinant Immunotoxin in Human Head and Neck Squamous Cell Carcinoma.
Antitumor Efficacy of EGFR-Targeted Recombinant Immunotoxin in Human Head and Neck Squamous Cell Carcinoma.
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DOI：
10.3390/biology11040486
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发表时间：
2022-03-22
期刊：
影响因子：
4.2
通讯作者：
Gu, Xinbin
中科院分区：
文献类型：
--
作者：
Xie, Guiqin;Shan, Liang;Liu, Yuanyi;Wu, Tzyy-Choou;Gu, Xinbin
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，每年诊断出超过50万例新病例。手术切除、放化疗、靶向治疗和免疫治疗已被批准用于HNSCC治疗。虽然少数患者经历了显著的长期和有利的临床反应，但大多数患者未能实现持久的临床反应。因此，迫切需要改进有益反应的替代方案。在HNSCC中，超过90%的肿瘤过表达细胞表面表皮生长因子受体（EGFR）。我们先前生产了人源化重组免疫毒素hDT 806，靶向肿瘤特异性过表达的EGFR和/或EGFRvIII突变体。在此，我们着手探索hDT 806在体外和体内环境中治疗HNSCC的作用和机制。我们发现hDT 806通过干扰EGFR信号传导、转录抑制、诱导细胞凋亡和DNA损伤在HNSCC中表现出显著的细胞毒性。超过90%的头颈部鳞状细胞癌（HNSCC）过表达表皮生长因子受体（EGFR）。然而，EGFR靶向单药治疗HNSCC的缓解率仅为10-30%。重组免疫毒素（RIT）通常由靶向肿瘤抗原的抗体和毒素（例如，白喉毒素[DT]）杀死癌细胞。我们产生了人源化RIT，命名为hDT 806，靶向过表达的EGFR，并研究了其在HNSCC中的作用。与EGFR靶向酪氨酸激酶抑制剂厄洛替尼或抗体西妥昔单抗不同，hDT 806有效地抑制了测试的四种HNSCC系（JHU-011、-013、-022和-029）中的细胞增殖。在JHU-029小鼠异种移植模型中，hDT 806显著降低肿瘤生长。hDT 806降低EGFR蛋白水平并破坏EGFR信号传导下游效应物，包括MAPK/ERK 1/2和AKT，同时增加促凋亡蛋白，如p53、caspase-9、caspase-3和裂解的PAPR。流式细胞仪分析证实hDT 806诱导的HNSCC细胞凋亡。此外，hDT 806导致对转录至关重要的RNA聚合酶II羧基末端结构域磷酸化的剧烈抑制和DNA损伤标记物γ H2 A. X水平的显著增加。因此，EGFR信号传导的直接破坏、转录抑制、DNA损伤以及由hDT 806诱导的细胞凋亡可能有助于其在HNSCC中的抗肿瘤功效。
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with more than 500,000 new cases diagnosed annually. Surgical resection, chemoradiotherapy, targeted therapy, and immunotherapy have been approved for HNSCC treatment. While a minority of patients experience dramatic long-lasting and favorable clinical responses, the majority of patients fail to achieve durable clinical responses. Thus, alternative options with improved beneficial response are urgently needed. In HNSCC, over 90% of tumors overexpress the cell surface epidermal growth factor receptor (EGFR). We previously produced a humanized recombinant immunotoxin, hDT806, targeting tumor-specific overexpressed EGFR and/or the EGFRvIII mutant. Here, we set out to explore the effects and mechanisms of hDT806 in treating HNSCC in both in vitro and in vivo settings. We found that hDT806 exhibits a significant cytotoxicity in HNSCC through disrupting EGFR signaling, transcription inhibition, and inducing apoptosis and DNA damage. Over 90% of head and neck squamous cell carcinoma (HNSCC) overexpresses the epidermal growth factor receptor (EGFR). However, the EGFR-targeted monotherapy response rate only achieves 10–30% in HNSCC. Recombinant immunotoxin (RIT) often consists of an antibody targeting a tumor antigen and a toxin (e.g., diphtheria toxin [DT]) that kills cancer cells. We produced a humanized RIT, designated as hDT806, targeting overexpressed EGFR and investigated its effects in HNSCC. Distinct from the EGFR-targeted tyrosine kinase inhibitor erlotinib or antibody cetuximab, hDT806 effectively suppressed cell proliferation in the four HNSCC lines tested (JHU-011, -013, -022, and -029). In JHU-029 mouse xenograft models, hDT806 substantially reduced tumor growth. hDT806 decreased EGFR protein levels and disrupted the EGFR signaling downstream effectors, including MAPK/ERK1/2 and AKT, while increased proapoptotic proteins, such as p53, caspase-9, caspase-3, and the cleaved PAPR. The hDT806-induced apoptosis of HNSCC cells was corroborated by flow cytometric analysis. Furthermore, hDT806 resulted in a drastic inhibition in RNA polymerase II carboxy-terminal domain phosphorylation critical for transcription and a significant increase in the γH2A.X level, a DNA damage marker. Thus, the direct disruption of EGFR signaling, transcription inhibition, DNA damage, as well as apoptosis induced by hDT806 may contribute to its antitumor efficacy in HNSCC.
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