ERBB4 encodes HER4, an EGFR receptor tyrosine kinase, which activates PI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathways to promote cell survival and proliferation. Simple ERBB4 variants are seen in 2.3% of all tumors, including with 15% of skin cancers, 6% of colorectal cancers, and 3% of lung cancers. Preclinical studies indicate that ERBB4 variants sensitize tumors to pan-EGFR family inhibitors.