Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1.

Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.