Multiple mechanisms of primary or acquired resistance to HER2-directed therapies are reported to be associated with several signal transduction molecules in breast cancer, including dysregulation of downstream PI3K/Akt/mTOR signaling, PTEN loss, TP53 mutations, abnormal activation of other HER2 coligands (HER3, EGFR, IGFR), additional upregulation of HER2 via acquired amplifications and/or somatic mutations, etc. [16–20]. The gene discussed is ERBB3; the disease is breast cancer.