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

Abstract

BACKGROUND:

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.

RESULTS:

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.

MATERIALS AND METHODS:

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.

CONCLUSIONS:

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.

• Authors: Yoshikane Nonagase, Kimio Yonesaka, Hisato Kawakami, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Junko Tanizaki, Hidetoshi Hayashi, Takeshi Yoshida, Masayuki Takeda, Yasutaka Chiba, Takao Tamura, Kazuhiko Nakagawa, Junji Tsurutani
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 51 Pg. 84860-84871 (Dec 20 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27768588 (Publication Type: Journal Article)

Chemical References

• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Neuregulin-1
• Quinazolines
• Survivin
• Lapatinib
• Maytansine
• ERBB2 protein, human
• ERBB3 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3
• Oncogene Protein v-akt
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine
• Aged
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Female
• Humans
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Lapatinib
• Male
• Maytansine (analogs & derivatives, therapeutic use)
• Middle Aged
• Neuregulin-1 (metabolism)
• Oncogene Protein v-akt (metabolism)
• Quinazolines (therapeutic use)
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-3 (metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy)
• Survivin
• Trastuzumab (therapeutic use)