Identification of Acquired Notch3 Dependency in Metastatic Head and Neck Cancer

Survival rates for patients with metastatic HNSCC remain low and with not effective available treatments. We conducted genomic and functional genomic analyses in matched sets of HNSCC cell lines derived from primary tumors and their respective metastatic sites. Components of the Notch3 pathway were identified as differentially expressed and essential in metastatic cells. A distinct gene set is induced upon Notch3/Jag2 interaction in metastatic cells and is associated with EMT. We identified an acquired mutation in the EGF domain of Notch3 in one of the metastatic lines and used CRISPR methodology to demonstrate that this mutation drove altered signaling and dependence in the metastatic variant. Finally, we show that suppression of Notch3 improves survival in mice bearing metastatic orthotropic tumors.