title: Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency.
abstract: Epidermal growth factor receptor (EGFR) blockade and radiation are efficacious in the treatment of cancer, but resistance is commonly reported. Studies have suggested that dysregulation of Notch signaling and enrichment of the cancer stem cell population underlie these treatment challenges. Our data show that dual targeting of EGFR and Notch2/3 receptors with antibody CT16 not only inhibited signaling mediated by these receptors but also showed a strong anti-stem cell effect both in vitro and in vivo. Treatment with CT16 prevented acquired resistance to EGFR inhibitors and radiation in non-small cell lung cancer (NSCLC) cell line models and patient-derived xenograft tumors. CT16 also had a superior radiosensitizing impact compared with EGFR inhibitors. CT16 in combination with radiation had a larger antitumor effect than the combination of radiation with EGFR inhibitors or tarextumab. Mechanistically, CT16 treatment inhibits the stem cell-like subpopulation, which has a high mesenchymal gene expression and DNA repair activity, and reduces tumor-initiating cell frequency. This finding highlights the capacity of a combined blockade of EGFR and Notch signaling to augment the response to radiation and suggests that CT16 may achieve clinical efficacy when combined with radiation in NSCLC treatment.
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. hus@smmu.edu.cn hus@aftertumor.com lei@smmu.edu.cn.
authors.forename: Shi
authors.identifier: 0000-0002-7905-4284
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200030, China.|Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai 200030, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qingning
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Gaojian
authors.initials: G
authors.lastname: Lv
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Fangxing
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xuting
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yongji
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. hus@smmu.edu.cn hus@aftertumor.com lei@smmu.edu.cn.
authors.forename: Changhai
authors.identifier: 0000-0003-1665-5215
authors.initials: C
authors.lastname: Lei
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051880:Receptors, Notch; D000444:Aldehyde Dehydrogenase; D066246:ErbB Receptors