Targeting EGFR Enriches Stem Cell-Like Properties in Salivary Adenoid Cystic Carcinoma by Activating the Notch1 Pathway

Yang Wang; Yong Han; Shengming Xu; Ling Zhang; Xiangkai Zhang; Jiong Deng; Weimin Ye; Shuli Liu

doi:10.2147/CMAR.S253500

Targeting EGFR Enriches Stem Cell-Like Properties in Salivary Adenoid Cystic Carcinoma by Activating the Notch1 Pathway

Cancer Manag Res. 2020 Jul 31:12:6655-6663. doi: 10.2147/CMAR.S253500. eCollection 2020.

Authors

Yang Wang^#^{1

2

3}, Yong Han^#^{1

3}, Shengming Xu^#^{1

3}, Ling Zhang^{1

3}, Xiangkai Zhang^{1

3}, Jiong Deng⁴, Weimin Ye^{1

3}, Shuli Liu^{1

2

3}

Affiliations

¹ 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.
² 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.
³ National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China.
⁴ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Bmi-1; EGFR; Notch1; SACC; erlotinib.