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Antitumor Activity of the Novel Oral Heat Shock Protein 90 Inhibitor in Mono Therapy and Combination Therapy

小野, 尚美 筑波大学 DOI:10.15068/00160401

2020.07.21

概要

Heat shock protein 90 (HSP90) is 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. It is an attractive target for cancer therapy. Recently, a novel HSP90 inhibitor (CH5164840) was identified, and its induction of oncogenic client protein degradation, anti- proliferative activity, and apoptosis investigated using the NCI-N87 gastric and BT-474 breast cancer cell lines. Interestingly, CH5164840 demonstrated tumor selectivity both in vitro and in vivo, binding to tumor HSP90, which forms active super chaperone complexes, rather than the HSP90 of normal cell, which mainly exist as non-complexes with co-chaperons in vitro. It is extensively distributed in mouse model tumors. These facts support the CH5164840-induced phosphorylated AKT level decrease observed in tumor tissues, but not in normal tissues. In addition to being well tolerated, orally administered CH5164840 exerts potent antitumor efficacy, leading to regression in the NCI-N87 and BT-474 tumor xenograft models. Additionally, CH5164840 significantly enhanced antitumor efficacy against the gastric and breast cancer models when co-administered with the human epidermal growth factor receptor 2 (HER2)-targeted agents trastuzumab and lapatinib. These data demonstrate the potential antitumor efficacy of monotherapy with CH5164840, and the significant synergistic efficacy of its co-administration with trastuzumab or lapatinib, validifying clinical development of CH5164840 as an HSP90 inhibitor for combination therapy with HER2-targeted agents against HER2- overexpressing tumors.

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 non-small-cell lung cancer (NSCLC) patients. However, primary and acquired resistance to existing EGFR inhibitors is a major clinical problem. In the present study, the antitumor activity of a combination of erlotinib and CH5164840 was investigated. The NSCLC cell lines and xenograft models were treated with CH5164840 and erlotinib to examine their mechanisms of action and cell growth inhibition. CH5164840 showed remarkable antitumor activity against the NSCLC cell lines and xenograft models. Combination therapy with CH5164840 enhanced the antitumor activity of erlotinib against NCI-H292 EGFR-overexpressing xenograft models. In vitro treatment of NCI-H292 cells with erlotinib resulted in increased STAT3 phosphorylation. Next, the role of the STAT3 signal in the mechanism of action of the erlotinib and CH5164840 combination was evaluated, as it is an important tumor growth-related signal. STAT3 phosphorylation increase in erlotinib-treated NCI-H292 cells was abrogated by HSP90 inhibition. Additionally, CH5164840 enhanced the antitumor activity of erlotinib, despite the low efficacy of erlotinib monotherapy, in a NCI-H1975 T790M mutation erlotinib-resistant model. Further, extracellular signal-regulated kinase (ERK) signaling was effectively suppressed by the erlotinib and CH5164840 co-therapy, in a NCI-H1975 erlotinib resistant model. These data collectively indicate the potent antitumor activity of CH5164840 and higher efficacy of its coadministration with erlotinib against NSCLC tumors with EGFR overexpression and mutations. Therefore, providing evidence of the therapeutic potential of CH5164840 as an HSP90 inhibitor for combination therapy with EGFR- targeting agents against EGFR-addicted NSCLC.

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