Combined Erlotinib and PF-03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma
Combined Erlotinib and PF-03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma
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厄洛替尼和 PF-03084014 联合治疗有助于头颈鳞状细胞癌的综合致死率
DOI：
10.1111/cpr.12424
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发表时间：
2018
影响因子：
8.5
通讯作者：
Song Xiaomeng
中科院分区：
文献类型：
--
作者：
Zheng Yang;Wang Zhao;Ding Xu;Dong Yibo;Zhang Wei;Zhang Wei;Zhong Yi;Gu Wenyi;Wu Yunong;Song Xiaomeng
目的头颈鳞状细胞癌（HNSCC）具有高死亡率和低生存率的特点。作为表皮生长因子受体（EGFR）抑制剂，厄洛替尼已被批准用于治疗多种肿瘤。 PF-03084014 是 Notch1 信号传导的选择性抑制剂。本研究旨在探索同时靶向 EGFR 和 Notch1 信号传导以减弱肿瘤生长并提高生存率的新方法。材料和方法通过 CCK-8 测定和流式细胞术测定细胞增殖。通过Transwell实验测定细胞侵袭能力。 Western blot检测Notch1和EGFR通路的表达。使用 Cleaved Caspase-3 染色和 TUNEL 检测来验证联合治疗的细胞凋亡。结果我们首次证实了厄洛替尼和 PF-03084014 联合治疗对 HNSCC 的增殖抑制和细胞死亡。此外，我们发现 PF-03084014 逆转了厄洛替尼诱导的侵袭增加。在体内临床前治疗药物试验中，联合治疗有效地抑制了肿瘤生长。最重要的是，发现一种机制，单独使用 PF-03084014 可以激活 PI3K/AKT 信号（EGFR 信号传导的下游），单独使用厄洛替尼可以激活 Notch1 的细胞内结构域（NICD），而 PF-03084014 和厄洛替尼联合治疗则抑制 HNSCC 的生长。结论这些结果表明，联合治疗 抑制 Notch1 和 EGFR 通路是促进 HNSCC 细胞凋亡和克服治疗耐药的合理策略。
ObjectivesHead and neck squamous cell carcinoma (HNSCC) is characterized by high mortality and low survival rates. As an epidermal growth factor receptor (EGFR) inhibitor, Erlotinib has been approved for treatment of various tumours. PF‐03084014 is a selective inhibitor of Notch1 signalling. This study aimed to explore new approaches for simultaneously targeting EGFR and Notch1 signalling to attenuate tumour growth and improve survival.Materials and methodsCell proliferation was determined by CCK‐8 assay and Flow cytometry. Cell invasive ability was determined by Transwell assay. Western blot was used to test the expression of Notch1 and EGFR pathway. Cleaved Caspase‐3 staining and TUNEL assay were used to verify the apoptosis through combined treatment.ResultsWe first confirmed proliferative inhibition and cell death in HNSCC with combined Erlotinib and PF‐03084014 treatment. Moreover, we found PF‐03084014 reversed the increased invasion induced by Erlotinib. In a preclinical therapeutic drug trial in vivo, combined treatment effectively abrogated tumour growth. Most importantly, one mechanism was found that PF‐03084014 alone could activate the PI3K/AKT signalling, the downstream of EGFR signalling, and Erlotinib alone could activate the intracellular domain of Notch1 (NICD), while combined treatment of PF‐03084014 and Erlotinib suppressed the HNSCC growth.ConclusionsThese results suggested that concomitant inhibition of the Notch1 and EGFR pathways represented a rational strategy for promoting apoptosis in HNSCC and overcoming treatment resistance.