Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA; Institute for Genome Sciences, University of Maryland Medical Center, Baltimore, MD, USA; Department of Otorhinolaryngology-Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Oral Oncol. 2022 Aug;131:105939. doi: 10.1016/j.oraloncology.2022.105939. Epub 2022 Jun 3.
To identify the most effective PI3K and EGFR inhibitors in HPV-positive head and neck squamous cell carcinoma (HNSCC) and investigate the efficacy of a combination of an ErbB family kinase inhibitor and a PI3K inhibitor to inhibit cell proliferation of HPV-positive HNSCC.
HPV-positive HNSCC cell lines were treated with the FDA approved ErbB kinase inhibitor, Afatinib or FDA-approved PI3K inhibitor, Copanlisib, alone or in combination, and phosphorylation and total protein levels of cells were assessed by Western blot analysis.Cell proliferation and apoptosis were examined by MTS assay, flow cytometry, and Western blots, respectively.
Copanlisib more effectively inhibited cell proliferation in comparison to other PI3K inhibitors tested. HPV-positive HNSCC cells differentially responded to cisplatin, Afatinib, or Copanlisib. The combination of Afatinib and Copanlisib more effectively suppressed cell proliferation and induced apoptosis compared to either treatment alone. Mechanistically, the combination of Afatinib and Copanlisib completely blocked phosphorylation of EGFR, HER2, HER3, and Akt as well as significantly decreased the HPV E7 expression compared to either treatment alone.
Afatinib and Copanlisib more effectively suppress cell proliferation and survival of HPV-positive HNSCC in comparison to either treatment alone.
鉴定 HPV 阳性头颈部鳞状细胞癌（HNSCC）中最有效的 PI3K 和 EGFR 抑制剂，并研究 ErbB 家族激酶抑制剂与 PI3K 抑制剂联合应用对抑制 HPV 阳性 HNSCC 细胞增殖的疗效。
用美国食品和药物管理局（FDA）批准的 ErbB 激酶抑制剂阿法替尼或 FDA 批准的 PI3K 抑制剂Copanlisib 单独或联合处理 HPV 阳性 HNSCC 细胞系，并通过 Western blot 分析评估细胞的磷酸化和总蛋白水平。通过 MTS 测定、流式细胞术和 Western blot 分别检测细胞增殖和凋亡。
Copanlisib 比其他测试的 PI3K 抑制剂更有效地抑制细胞增殖。HPV 阳性 HNSCC 细胞对顺铂、阿法替尼或 Copanlisib 的反应不同。与单独治疗相比，阿法替尼和 Copanlisib 的联合治疗更有效地抑制细胞增殖并诱导凋亡。从机制上讲，与单独治疗相比，阿法替尼和 Copanlisib 的联合治疗完全阻断了 EGFR、HER2、HER3 和 Akt 的磷酸化，并显著降低了 HPV E7 的表达。
与单独治疗相比，阿法替尼和 Copanlisib 更有效地抑制 HPV 阳性 HNSCC 的细胞增殖和存活。
