A recent report associates trastuzumab resistance with activation of a RET-HER2 signaling axis, whereas trastuzumab-naïve cells rely on a RET-SRC-HER2 signaling (161), suggesting that trastuzumab resistance may be a consequence of Src-independent signaling in HER2-enriched breast cancers that have concurrent RET activation. The gene discussed is ERBB2; the disease is breast cancer.