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|Ref Type||Journal Article|
|Authors||Hu S, Fu W, Li T, Yuan Q, Wang F, Lv G, Lv Y, Fan X, Shen Y, Lin F, Tang Y, Ye X, Yang Y, Lei C|
|Title||Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency.|
|Journal||Science translational medicine|
|Date||2017 Mar 08|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CT16||EGFR Antibody 30 NOTCH2 Antibody 3 NOTCH3 Antibody 2||CT16 is an antibody that targets both EGFR and NOTCH2/3, resulting in decreased ligand binding and downstream signaling, and potentially leading to decreased tumor growth and increased sensitivity to radiotherapy (PMID: 28275151).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||lung cancer||not applicable||CT16||Preclinical - Pdx||Actionable||In a preclinical study, CT16 treatment decreased NOTCH and EGFR signaling and inhibited tumor growth in lung cancer patient-derived xenograft (PDX) models sensitive to EGFR blockade (PMID: 28275151).||28275151|