Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α
Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α
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DOI：
10.1038/s41416-019-0394-9
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发表时间：
2019-03-19
影响因子：
8.8
通讯作者：
Chiocca, Susanna
中科院分区：
文献类型：
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作者：
Citro, Simona;Bellini, Alice;Chiocca, Susanna
背景技术背景：表皮生长因子受体（EGFR）的过度表达与头颈癌（HNC）的发展有关，并代表了这种疾病的主要治疗靶点之一。EGFR抑制剂的使用由于其原发性和获得性抗性而具有有限的功效，部分原因是上皮向间充质转化（EMT）增加。HDAC抑制剂SAHA已被证明可以逆转不同肿瘤中的EMT，包括HNC。在这项研究中，我们研究了SAHA和EGFR酪氨酸激酶抑制剂吉非替尼在HPV阳性和HPV阴性HNC细胞株中的协同作用。方法：一组12个HPV阳性和HPV阴性HNC细胞株进行了筛选，用SAHA，吉非替尼和两者的组合治疗后的细胞活力。在SAHA处理后评估上皮/间充质标志物表达以及信号传导途径的激活。用shRNA慢病毒颗粒沉默Δ Np 63 α，以确定其在细胞增殖，迁移和TGF β途径activation.Results的作用：我们发现，无论是SAHA和吉非替尼在HPV阳性和HPV阴性HNC细胞系的抗肿瘤活性，它们的组合具有协同作用，抑制细胞生长。SAHA治疗逆转EMT并抑制转录因子Delta Np 63 α的表达。抑制三角洲Np 63 α降低EGFR蛋白水平，并减少细胞增殖和TGF β依赖性迁移在HPV阳性和HPV阴性HNC细胞line.CONCLUSIONS：我们的研究结果，通过给一个明确的分子机制的基础上的SAHA在HNC细胞系的抗肿瘤活性，提供了一个合理的SAHA与吉非替尼在HPV阳性和HPV阴性HNC患者的临床评价。进一步的知识是关键，以设计额外的线的组合治疗策略，这种疾病。
BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is associated with the development of head and neck cancer (HNC) and represents one of the main therapeutic targets for this disease. The use of EGFR inhibitors has limited efficacy due to their primary and acquired resistance, partially because of increased epithelial to mesenchymal transition (EMT). The HDAC inhibitor SAHA has been shown to revert EMT in different tumours, including HNC. In this study, we investigated the cooperative role of SAHA and the EGFR tyrosine kinase inhibitor gefitinib in both HPV-positive and HPV-negative HNC cell lines.METHODS: A panel of 12 HPV-positive and HPV-negative HNC cell lines were screened for cell viability upon treatment with SAHA, gefitinib and the combination of the two. Epithelial/mesenchymal marker expression, as well as activation of signalling pathway, were assessed upon SAHA treatment. Delta Np63 alpha silencing with shRNA lentiviral particles was used to determine its role in cell proliferation, migration and TGF beta pathway activation.RESULTS: We found that both SAHA and gefitinib have antitumour activity in both HPV-positive and HPV-negative HNC cell lines and that their combination has a synergistic effect in inhibiting cell growth. SAHA treatment reverts EMT and inhibits the expression of the transcription factor Delta Np63 alpha. Suppression of Delta Np63 alpha reduces EGFR protein levels and decreases cell proliferation and TGF beta-dependent migration in both HPV-positive and HPV-negative HNC cell lines.CONCLUSIONS: Our results, by giving a clear molecular mechanism at the basis of the antitumour activity of SAHA in HNC cell lines, provide a rationale for the clinical evaluation of SAHA in combination with gefitinib in both HPV-positive and HPV-negative HNC patients. Further knowledge is key to devising additional lines of combinatorial treatment strategies for this disease.