Schulz Dominik, Wirth Markus, Piontek Guido, Buchberger Anna Maria Stefanie, Schlegel Jürgen, Reiter Rudolf, Multhoff Gabriele, Pickhard Anja
Department of Otolaryngology Head and Neck Surgery, Technical University of Munich Ismaninger Straße 22, Munich, Germany.
Division of Neuropathology, Institute of Pathology, Technical University of Munich Ismaninger Straße 22, Munich, Germany.
Am J Cancer Res. 2016 Sep 1;6(9):1963-1975. eCollection 2016.
Despite remarkable successes with targeted therapies in the treatment of cancer, resistance can occur which limits the clinical outcome. In this study, we generated and characterized resistant cell clones derived from two different head and neck squamous cell carcinoma (HNSCC) cell lines (Cal27, UD-SCC-5) by long-term exposure to five targeted- and chemotherapeutics (afatinib, MK2206, BEZ235, olaparib and cisplatin). The resistant tumor cell clones showed an increased ERK1/2 expression and an altered expression of the stem-cell markers CD44, ALDH1, Oct4, Sox2, Nanog and Bmi1. None of the single markers alone was predictive for resistance to all five targeted- and chemotherapeutics. Furthermore, long-term exposure of tumor cells to these five drugs resulted in an eightfold increase in the mutational rate compared to untreated cells. Interestingly, targeted- and chemotherapy resistant cell clones remained sensitive to irradiation. Lastly, clones that were resistant to afatinib, MK2206 or BEZ235 showed cross-resistance to further treatment with therapeutics that affect the same signaling pathway, but remained sensitive to those affecting different pathways such as cisplatin and olaparib. In contrast, cell clones which were once resistant to cisplatin or olaparib were found to be multidrug-resistant. These data might indicate that patients with HNSCC benefit more by a first line targeted therapy followed by cisplatin as a second line therapy.
尽管靶向疗法在癌症治疗中取得了显著成功，但仍可能出现耐药性，这限制了临床疗效。在本研究中，我们通过长期暴露于五种靶向治疗药物和化疗药物（阿法替尼、MK2206、BEZ235、奥拉帕尼和顺铂），从两种不同的头颈部鳞状细胞癌（HNSCC）细胞系（Cal27、UD-SCC-5）中生成并鉴定了耐药细胞克隆。耐药肿瘤细胞克隆显示ERK1/2表达增加，干细胞标志物CD44、ALDH1、Oct4、Sox2、Nanog和Bmi1的表达发生改变。没有单一标志物能够单独预测对所有五种靶向治疗药物和化疗药物的耐药性。此外，与未处理的细胞相比，肿瘤细胞长期暴露于这五种药物导致突变率增加了八倍。有趣的是，靶向治疗和化疗耐药的细胞克隆对辐射仍敏感。最后，对阿法替尼、MK2206或BEZ235耐药的克隆对影响相同信号通路的其他治疗药物进一步治疗表现出交叉耐药性，但对影响不同通路的药物如顺铂和奥拉帕尼仍敏感。相反，曾经对顺铂或奥拉帕尼耐药的细胞克隆被发现具有多药耐药性。这些数据可能表明，HNSCC患者一线采用靶向治疗，二线采用顺铂治疗可能获益更多。
