Wang Yang, Han Yong, Xu Shengming, Zhang Ling, Zhang Xiangkai, Deng Jiong, Ye Weimin, Liu Shuli
Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Cancer Manag Res. 2020 Jul 31;12:6655-6663. doi: 10.2147/CMAR.S253500. eCollection 2020.
Salivary adenoid cystic carcinoma (SACC), a rare cancer arising in the salivary glands, is characterized by high rates of relapse and distant metastasis. Epidermal growth factor receptor (EGFR) has been implicated in SACC carcinogenesis. However, prospective trials of EGFR-targeting therapies in SACC are limited, and the optimum regimen is unclear.
The effects of erlotinib on cell proliferation, colony formation, ALDH enzymatic activity and tumorsphere formation were investigated in SACC cells. Expression of the cancer stem cell markers Bmi-1 and Oct4 was evaluated using Western blotting.
We found that while it robustly inhibited cell growth, targeting EGFR with erlotinib enriched the ALDH cell population and elevated the clonogenicity of SACC cells, suggesting an increase in stem cell-like potential. In addition, we found that suppression of EGFR kinase activity with erlotinib led to the activation of Notch1 signaling, leading to an increase in stem cell-like properties. Moreover, the γ-secretase inhibitor GSI treatment eliminated the erlotinib-induced increase in stem cell-like properties by decreasing Notch activity.
Our results provide an explanation for the worsened survival observed in some studies of erlotinib therapy in SACC and provide potential therapeutic strategies by combined blockade of the EGFR and Notch1 pathways.
涎腺腺样囊性癌（SACC）是一种起源于涎腺的罕见癌症，其特点是复发率和远处转移率高。表皮生长因子受体（EGFR）与SACC的致癌作用有关。然而，EGFR靶向治疗在SACC中的前瞻性试验有限，最佳治疗方案尚不清楚。
研究了厄洛替尼对SACC细胞增殖、集落形成、醛脱氢酶（ALDH）活性和肿瘤球形成的影响。使用蛋白质印迹法评估癌症干细胞标志物Bmi-1和Oct4的表达。
我们发现，虽然厄洛替尼强烈抑制细胞生长，但用其靶向EGFR会使ALDH细胞群体富集，并提高SACC细胞的克隆形成能力，这表明干细胞样潜能增加。此外，我们发现用厄洛替尼抑制EGFR激酶活性会导致Notch1信号通路激活，从而增加干细胞样特性。此外，γ-分泌酶抑制剂GSI处理通过降低Notch活性消除了厄洛替尼诱导的干细胞样特性增加。
我们的结果解释了在一些SACC厄洛替尼治疗研究中观察到的生存率恶化情况，并通过联合阻断EGFR和Notch1通路提供了潜在的治疗策略。
