Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain.
Molecular Oncology, University Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain.
Int J Mol Sci. 2018 Jun 21;19(7):1824. doi: 10.3390/ijms19071824.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and although new therapeutic approaches have been recently evaluated, overall patient survival is still poor. Thus, new effective and selective clinical treatments are urgently needed. An analysis of data from large-scale, high-throughput drug screening cell line projects identified Bosutinib, a Src/Abl inhibitor that is currently used for the treatment of chronic myelogenous leukemia, as a candidate drug to treat HNSCC. Using a panel of HNSCC-derived cell lines, we found that treatment with Bosutinib reduced cell proliferation and induced apoptosis of sensitive cell lines. The drug rapidly inhibited Src and EGFR (epidermal growth factor receptor) phosphorylation, and sensitivity to Bosutinib was correlated with the activation status of EGFR. Similar findings were observed in in vivo xenograft assays using HNSCC derived cells. Moreover, in the presence of mutations in , the combination of Bosutinib with the PI3Kα inhibitor Alpelisib showed a synergistic effect. These results suggest that Bosutinib could be a new effective drug for the treatment of HNSCC, particularly in tumors with high EGFR activity. Its combination with Alpelisib could especially benefit patients bearing activating mutations of .
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，尽管最近已经评估了新的治疗方法，但总体患者生存率仍然较低。因此，迫切需要新的有效和选择性的临床治疗方法。对大规模高通量药物筛选细胞系项目数据的分析表明，博舒替尼（一种目前用于治疗慢性髓性白血病的Src/Abl 抑制剂）是一种治疗 HNSCC 的候选药物。使用一组 HNSCC 衍生的细胞系，我们发现博舒替尼治疗可降低细胞增殖并诱导敏感细胞系凋亡。该药物可迅速抑制Src 和 EGFR（表皮生长因子受体）磷酸化，对博舒替尼的敏感性与 EGFR 的激活状态相关。在使用源自 HNSCC 的细胞的体内异种移植测定中观察到了类似的发现。此外，在存在 突变的情况下，博舒替尼与 PI3Kα 抑制剂 Alpelisib 的联合使用显示出协同作用。这些结果表明，博舒替尼可能是治疗 HNSCC 的一种新的有效药物，特别是在 EGFR 活性高的肿瘤中。其与 Alpelisib 的联合使用可能特别有益于携带激活突变的患者。
