Previously, preclinical studies have suggested that heregulin may cause resistance to first-generation EGFR-TKIs such as erlotinib in NSCLC patients harboring EGFR-activating mutations, as heregulin promotes HER2-HER3 coupling and activates anti-apoptotic HER2-HER3-Akt bypass signaling27. This evidence concerns the gene ERBB3 and non-small cell lung carcinoma.