Proto-oncogene tyrosine-protein kinase Src plays an important role in Head and Neck Squamous Cell Carcinoma (HNSCC). However, the FDA-approved SRC inhibitor Dasatinib shows very limited efficacy in HNSCC clinical trials, even though Dasatinib can completely inhibit SRC in the laboratory setting. These results suggest that SRC inhibition can cause compensatory up-regulation and/or activation of other survival pathways, which suggests that co-targeting of SRC and the potential signaling pathways may improve the Dasatinib efficacy. In this study, we investigated the role of IKKβ/NF-κB in regulation of the sensitivity of cisplatin-resistant HNSCC to Dasatinib. Additionally, we wished to determine whether inhibition of the IKKβ/NF-κB signaling pathway could enhance Dasatinib efficacy to inhibit cisplatin-resistant HNSCC without the use of cisplatin. Previous studies have shown that ETS-1 is a crucial SRC effector protein that regulates cancer cell proliferation, anti-apoptosis, and metastasis. We found that SRC kinase inhibition by Dasatinib decreased ETS-1 expression but caused elevation of IKKβ/NF-κB signaling in multiple cisplatin-resistant HNSCC. Interestingly, inhibition of IKKβ/NF-κB by CmpdA (Bay65-1942), a recently identified IKKβ inhibitor, also led to a decrease in ETS-1 levels. Moreover, the knockdown of IKK, but not NF-κB, dramatically decreased ETS-1 expression. In addition, IKKβ and ETS-1 interacted in cisplatin-resistant HNSCC. These data demonstrated cross-talk between SRC and IKK to regulate NF-κB and ETS-1. Furthermore, we found that simultaneous inhibition of SRC and IKKβ through a Dasatinib and CmpdA combination synergistically inhibited NF-κB activation and ETS-1expression, suppressed cell proliferation, and induced apoptosis. Taken together, our data indicate that SRC and IKKβ play crucial roles in cisplatin-resistant HNSCCC and co-targeting SRC and IKKβ could be an effective strategy to treat cisplatin-resistant HNSCC.

中文翻译：

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抑制 IKKβ/NF-κB 信号通路可提高达沙替尼抑制顺铂耐药头颈鳞状细胞癌的疗效。

原癌基因酪氨酸蛋白激酶Src在头颈鳞状细胞癌（HNSCC）中发挥重要作用。然而，FDA批准的SRC抑制剂达沙替尼在HNSCC临床试验中显示的疗效非常有限，尽管达沙替尼在实验室环境中可以完全抑制SRC。这些结果表明，SRC 抑制可导致其他生存途径的代偿性上调和/或激活，这表明 SRC 和潜在信号传导途径的共同靶向可能会提高达沙替尼的疗效。在本研究中，我们研究了 IKKβ/NF-κB 在调节顺铂耐药 HNSCC 对达沙替尼敏感性中的作用。此外，我们希望确定抑制 IKKβ/NF-κB 信号通路是否可以增强达沙替尼在不使用顺铂的情况下抑制顺铂耐药 HNSCC 的功效。此前的研究表明，ETS-1是调节癌细胞增殖、抗凋亡和转移的重要SRC效应蛋白。我们发现达沙替尼抑制 SRC 激酶会降低 ETS-1 表达，但会导致多种顺铂耐药 HNSCC 中 IKKβ/NF-κB 信号传导升高。有趣的是，最近发现的 IKKβ 抑制剂 CmpdA (Bay65-1942) 对 IKKβ/NF-κB 的抑制也会导致 ETS-1 水平下降。此外，IKK（而非 NF-κB）的敲低显着降低了 ETS-1 的表达。此外，IKKβ 和 ETS-1 在顺铂耐药的 HNSCC 中相互作用。这些数据证明了 SRC 和 IKK 之间的串扰来调节 NF-κB 和 ETS-1。此外，我们发现通过达沙替尼和 CmpdA 组合同时抑制 SRC 和 IKKβ 可协同抑制 NF-κB 激活和 ETS-1 表达，抑制细胞增殖并诱导细胞凋亡。综上所述，我们的数据表明，SRC 和 IKKβ 在顺铂耐药性 HNSCC 中发挥着至关重要的作用，联合靶向 SRC 和 IKKβ 可能是治疗顺铂耐药性 HNSCC 的有效策略。