拉帕替尼的细胞毒性作用仅限于人乳头瘤病毒阳性的头颈部鳞状细胞癌细胞系。
Cytotoxic effect of lapatinib is restricted to human papillomavirus-positive head and neck squamous cell carcinoma cell lines.
机构信息
Inserm U1030, Molecular Radiotherapy, LABEX LERMIT, Gustave Roussy, University Paris XI, Villejuif, France ; Radiation Therapy Department, Oscar Lambret Comprehensive Cancer Center, Lille, France.
Inserm U1030, Molecular Radiotherapy, LABEX LERMIT, Gustave Roussy, University Paris XI, Villejuif, France.
出版信息
Onco Targets Ther. 2015 Feb 2;8:335-45. doi: 10.2147/OTT.S68235. eCollection 2015.
BACKGROUND
Lapatinib is a dual epidermal growth factor receptor (EGFR) and HER2 inhibitor. Overexpression of these receptors is frequently observed in head and neck squamous cell carcinoma (HNSCC). As growing proportion of HNSCC is characterized by human papillomavirus (HPV) infection, we aimed at evaluating the efficacy of lapatinib as function of HPV status in HNSCC cell lines.
METHODS
Two HPV-positive and two HPV-negative HNSCC cell lines were used. Proliferation, cell cycle, and Annexin V assays were performed to test their sensitivity to lapatinib. Combination of lapatinib and ionizing radiation was evaluated with clonogenic survival assays. Akt, EGFR and HER2, and E6/E7 expression and activation were analyzed by immunoblotting and quantitative reverse transcription polymerase chain reaction.
RESULTS
Lapatinib reduced E6 and E7 expression and Akt phosphorylation, inhibited cell proliferation and induced cell death in HPV-positive cell lines. An additive effect of lapatinib with radiation was observed in these cells. Lapatinib had no effect on HPV-negative cells.
CONCLUSION
Lapatinib efficacy restricted to the HPV-positive cells suggests that HPV status could be a potential marker for enhanced response to lapatinib in HNSCC.
背景
拉帕替尼是一种双重表皮生长因子受体（EGFR）和 HER2 抑制剂。这些受体在头颈部鳞状细胞癌（HNSCC）中经常过表达。由于越来越多的 HNSCC 具有人乳头瘤病毒（HPV）感染的特征，我们旨在评估拉帕替尼在 HPV 状态下对头颈部鳞状细胞癌细胞系的疗效。
方法
使用两种 HPV 阳性和两种 HPV 阴性的 HNSCC 细胞系。通过增殖、细胞周期和 Annexin V 测定来测试它们对拉帕替尼的敏感性。通过集落形成存活测定评估拉帕替尼与电离辐射的联合作用。通过免疫印迹和定量逆转录聚合酶链反应分析 Akt、EGFR 和 HER2 以及 E6/E7 的表达和激活。
结果
拉帕替尼降低了 HPV 阳性细胞系中 E6 和 E7 的表达和 Akt 磷酸化，抑制了细胞增殖并诱导细胞死亡。在这些细胞中观察到拉帕替尼与辐射的相加作用。拉帕替尼对 HPV 阴性细胞没有影响。
结论
拉帕替尼的疗效仅限于 HPV 阳性细胞，这表明 HPV 状态可能是 HNSCC 中对拉帕替尼增强反应的潜在标志物。
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