Open AccessPreclinical antitumor activity of the novel heat shock protein 90 inhibitor CH5164840 against human epidermal growth factor receptor 2 (HER2)‐overexpressing cancers
Author(s) -
Ono Naomi,
Yamazaki Toshikazu,
Nakanishi Yoshito,
Fujii Toshihiko,
Sakata Kiyoaki,
Tachibana Yukako,
Suda Atsushi,
Hada Kihito,
Miura Takaaki,
Sato Shigeo,
Saitoh Ryoichi,
Nakano Kohnosuke,
Tsukuda Takuo,
Mio Toshiyuki,
Ishii Nobuya,
Kondoh Osamu,
Aoki Yuko
Publication year - 2012
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/j.1349-7006.2011.02144.x
Subject(s) - heat shock protein , human epidermal growth factor receptor 2 , epidermal growth factor receptor , cancer research , epidermal growth factor , growth factor receptor inhibitor , pharmacology , heat shock factor , medicine , receptor , biology , chemistry , cancer , hsp70 , biochemistry , gene , breast cancer
Heat shock protein 90 (Hsp90), a molecular chaperone that plays a significant role in the stability and maturation of client proteins, including oncogenic targets for cell transformation, proliferation, and survival, is an attractive target for cancer therapy. We identified the novel Hsp90 inhibitor, CH5164840, and investigated its induction of oncogenic client protein degradation, antiproliferative activity, and apoptosis against an NCI‐N87 gastric cancer cell line and a BT‐474 breast cancer cell line. Interestingly, CH5164840 demonstrated tumor selectivity both in vitro and in vivo , binding to tumor Hsp90 (which forms active multiple chaperone complexes) in vitro , and being distributed effectively to tumors in a mouse model, which, taken together, supports the decreased levels of phosphorylated Akt by CH5164840 that we observed in tumor tissues, but not in normal tissues. As well as being well tolerated, the oral administration of CH5164840 exhibited potent antitumor efficacy with regression in NCI‐N87 and BT‐474 tumor xenograft models. In addition, CH5164840 significantly enhanced antitumor efficacy against gastric and breast cancer models when combined with the human epidermal growth factor receptor 2 (HER2)‐targeted agents, trastuzumab and lapatinib. These data demonstrate the potent antitumor efficacy of CH5164840 when administered alone, and its significant combination efficacy when combined with trastuzumab or lapatinib, supporting the clinical development of CH5164840 as an Hsp90 inhibitor for combination therapy with HER2‐targeted agents against HER2‐overexpressing tumors. ( Cancer Sci 2012; 103: 342–349)