Research ArticleCancer

Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency

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Science Translational Medicine  08 Mar 2017:
Vol. 9, Issue 380, eaag0339
DOI: 10.1126/scitranslmed.aag0339

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Two targets for a bigger punch

The epidermal growth factor receptor (EGFR) is a common target of therapeutics for a variety of different tumors, but tumors eventually become resistant to these drugs. One route to resistance is an increase in the number of cancer stem cells driven by the Notch pathway. To overcome this type of resistance, Hu et al. created a customized antibody called CT16, which can recognize both EGFR and Notch, simultaneously inhibiting both pathways. The authors tested this antibody in mouse models of non–small cell lung cancer, showing that it inhibits cancer stem cells and is more effective than antibodies against the individual pathways alone and in combination, particularly in the presence of radiation treatment.

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.

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