Ando et al show in head and neck squamous cell carcinoma cells that EGFR activation leads to the phosphorylation of the Hippo pathway component, MOB1 to inhibit LATS1/2 function resulting in YAP/TAZ activation. Further, EGFR-targeting therapies suppress YAP/TAZ, and loss of LATS1/2-mediated YAP/TAZ activation confers therapy resistance, thus offering insights into potential drug resistance mechanisms in cancers with activated EGFR.