Open AccessAntitumor activity of pan‐ HER inhibitors in HER 2‐positive gastric cancer
Author(s) -
Yoshioka Takahiro,
Shien Kazuhiko,
Namba Kei,
Torigoe Hidejiro,
Sato Hiroki,
Tomida Shuta,
Yamamoto Hiromasa,
Asano Hiroaki,
Soh Junichi,
Tsukuda Kazunori,
Nagasaka Takeshi,
Fujiwara Toshiyoshi,
Toyooka Shinichi
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13546
Subject(s) - neratinib , afatinib , cancer , cancer research , trastuzumab , targeted therapy , cancer cell , medicine , epidermal growth factor receptor , lapatinib , cell culture , growth inhibition , pharmacology , biology , erlotinib , breast cancer , genetics
Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti‐human epidermal growth factor receptor 2 ( HER 2) drugs have been developed, trastuzumab is still the only anti‐ HER 2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER 2‐positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan‐ HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER 2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER 2 ‐amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP 7 , a tumor suppressor gene that inhibits the activation of insulin‐like growth factor‐1 receptor ( IGF ‐1R), were less sensitive to pan‐ HER inhibitors. A combination therapy consisting of pan‐ HER inhibitors and an IGF ‐1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER 2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER 2 ‐amplified gastric cancer. In addition to HER 2 amplification, IGFBP 7 might be a biomarker of sensitivity to these drugs, and IGF ‐1R ‐targeting therapy can overcome drug insensitiveness in HER 2 ‐amplified gastric cancer.