Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non-small-cell lung cancer.

Abstract

Inhibition of heat shock protein 90 (Hsp90) can lead to degradation of multiple client proteins, which are involved in tumor progression. Epidermal growth factor receptor (EGFR) is one of the most potent oncogenic client proteins of Hsp90. Targeted inhibition of EGFR has shown clinical efficacy in the treatment of patients with non-small-cell lung cancer (NSCLC). However, primary and acquired resistance to the existing EGFR inhibitors is a major clinical problem. In the present study, we investigated the effect of the novel Hsp90 inhibitor CH5164840 on the antitumor activity of erlotinib. The NSCLC cell lines and xenograft models were treated with CH5164840 and erlotinib to examine their mechanisms of action and cell growth inhibition. We found that CH5164840 showed remarkable antitumor activity against NSCLC cell lines and xenograft models. The addition of CH5164840 enhanced the antitumor activity of erlotinib against NCI-H292 EGFR-overexpressing xenograft models. Phosphorylation of Stat3 increased with erlotinib treatment in NCI-H292 cells, which was abrogated by Hsp90 inhibition. Furthermore, in a NCI-H1975 T790M mutation erlotinib-resistant model, CH5164840 enhanced the antitumor activity of erlotinib despite the low efficacy of erlotinib treatment alone. In addition, ERK signaling was effectively suppressed by combination treatment with erlotinib and CH5164840 in a NCI-H1975 erlotinib-resistant model. Taken together, these data indicate that CH5164840 has potent antitumor activity and is highly effective in combination with erlotinib against NSCLC tumors with EGFR overexpression and mutations. Our results support the therapeutic potential of CH5164840 as a Hsp90 inhibitor for combination therapy with EGFR-targeting agents against EGFR-addicted NSCLC.

• Authors: Naomi Ono, Toshikazu Yamazaki, Toshiyuki Tsukaguchi, Toshihiko Fujii, Kiyoaki Sakata, Atsushi Suda, Takuo Tsukuda, Toshiyuki Mio, Nobuya Ishii, Osamu Kondoh, Yuko Aoki
• Journal: Cancer science (Cancer Sci) Vol. 104 Issue 10 Pg. 1346-52 (Oct 2013) ISSN: 1349-7006 [Electronic] England
• PMID: 23863134 (Publication Type: Journal Article)
• Copyright: © 2013 Japanese Cancer Association.

Chemical References

• Benzoquinones
• CH5164840
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Neoplasm Proteins
• Quinazolines
• STAT3 Transcription Factor
• STAT3 protein, human
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• JAK1 protein, human
• Janus Kinase 1

Topics

• Animals
• Benzoquinones (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor (drug effects)
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Janus Kinase 1 (metabolism)
• Lactams, Macrocyclic (pharmacology)
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (antagonists & inhibitors)
• Neoplasm Transplantation
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)
• Quinazolines (pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Xenograft Model Antitumor Assays