Persistent EGFR signaling, coupled with the autocrine induction of membrane-bound HRG, contributed to a switch in the regulation of cell survival from HER2-HER3-PI3K in treatment-naïve HER2+ breast cancer cells to an HRG-driven EGFR-HER3-PI3K-PDK1 signaling axis in lapatinib-resistant tumor cells. The gene discussed is HRG; the disease is breast carcinoma.