Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer

doi:10.1016/j.canlet.2011.01.010

Cancer Letters

Volume 302, Issue 2, 28 March 2011, Pages 155-165

https://doi.org/10.1016/j.canlet.2011.01.010 Get rights and content

Abstract

Trastuzumab, a HER2 directed treatment has shown clinical benefit in HER2 amplified gastric cancer. This study demonstrated the potent antitumor activity of HM781-36B, a quinazoline-based irreversible pan-HER inhibitor, in HER2 amplified gastric cancer cells (SNU216 and N87) in vitro and in vivo. HM781-36B inhibited phosphorylation of HER family and downstream signaling molecules, and induced apoptosis and G1 arrest. Furthermore, HM781-36B exerted synergistic effects with chemotherapeutic agents in both HER2 amplified and HER2 non-amplified gastric cancer cells. Therefore, HM781-36B may be useful for the treatment of HER2 amplified gastric cancer alone or in combination with chemotherapeutic agents.

Introduction

A signaling network of epidermal growth factor receptors (EGFR/HER1, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4) plays a key role in the regulation of cell proliferation and differentiation of many types of tissues [1], [2]. After the binding of receptor specific ligands, these receptors form homodimers or heterodimers with each other, which leads to the activation of intrinsic kinase through phosphorylation and subsequent activation of downstream signaling molecules [3]. Accordingly, the epidermal growth factor receptor family has been a major target of anticancer drugs, and two classes of drugs are known to interfere with their function. One of these classes is composed of monoclonal antibodies such as cetuximab, which competitively binds to EGFR [4], and trastuzumab and pertuzumab, which binds to the extracellular regions of HER2. The other class of drugs is composed of tyrosine kinase inhibitors (TKIs), which can inhibit the catalytic kinase function of the HER family. These drugs include EGFR-specific inhibitors such as gefitinib and erlotinib [5], [6], [7]. TKIs also include the dual reversible inhibitor of EGFR and HER2 such as lapatinib [8], [9], [10], [11], [12]. Furthermore, recent studies have shown that treatment with BIBW-2992, an irreversible dual inhibitor of EGFR and HER2 tyrosine kinase, might overcome gefitinib resistance via T790 M mutation [13], [14].

The effects of many pan-HER inhibitors, including CI-1033, PF00299804, BMS-599626, BMS-690514 (a novel pan-HER/VEGFR inhibitor) and JNJ-28871063 (a nonquinazoline pan-ErbB inhibitor), have been established. CI-1033 is a first-generation irreversible pan-HER inhibitor, while PF00299804 is a second generation inhibitor that has more attractive pharmacokinetic properties than CI-1033 due to its greater bioavailability, longer half-life and lower clearance. Indeed, PF00299804 is currently under clinical development and its efficacy in lung cancer models has been reported. [15], [16], [17], [18], [19]. However, there have been no studies conducted to evaluate the efficacy of pan-HER inhibitors against gastric cancer cells to date.

The studies described herein were therefore designed to investigate the cytotoxic effects of HM781-36B, a quinazoline-based pan-HER inhibitor, in gastric cancer cells when it was administered alone or in combination with clinically relevant cytotoxic chemotherapeutic agents (5-FU, cisplain, oxaliplatin, paclitaxel, docetaxel and SN-38).

Section snippets

Reagents

The quinazoline-based irreversible pan-HER inhibitor, HM781-36B, and other HER TKIs including Erlotinib, Gefitinib, Lapatinib, BIBW-2992 and CI-1033 were supplied by the Hanmi Pharmaceutical Company. Trastuzumab was obtained from Roche Korea Co., Ltd. (Seoul, Korea). In addition, the other following chemotherapeutic agents were obtained: 5-FU from Ildong Pharmaceutical Co., Ltd. (Seoul, Korea), cisplatin from Choongwoe Co., Ltd. (Seoul, Korea), paclitaxel from Samyang Co., Ltd. (Seoul, Korea),

HM781-36B is a specific inhibitor of HER family kinases

We examined the specificity of the pan-HER inhibitor, HM781-36B, by conducting in vitro kinase assays against purified HER family kinases. HM781-36B effectively inhibited HER family kinases with IC₅₀ values of 0.0032, 0.0053 and 0.0235 μmol/L and showed more potent inhibitory activity against both EGFR and HER2 compared to other HER family tyrosine kinase inhibitors such as gefitinib and BIBW-2992 (Table 1). In addition, HM781-36B more potently inhibited the activity of EGFR and HER2 than

Discussion

HER2 is encoded by a single gene on human chromosome 17. HER2 gene amplification and protein overexpression are observed in 20–30% of breast cancers and 5–25% of human gastric cancers and this is a prognostic indicator for poor outcome [9], [26], [27], [28], [29], [30]. EGFR and HER3 each form heterodimers with HER2, and these coreceptors subsequently drive HER2 amplified cancer. The role of EGFR in HER2 amplified tumors has been investigated using EGFR-specific TKIs [31] and the role of HER3

Conflicts of interest

Yung-Jue Bang: consultant/advisory board from Hanmi Inc. The other authors disclosed no potential conflicts of interest.

Acknowledgements

This work was supported by Grants from the Hanmi Pharmaceutical Company (06-2006-275-0) and in part from the Korean Healthcare21 and technology R&D project, Ministry for Health, Welfare & Family Affairs (A091081) and in part from the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0093820).

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Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer

Abstract

Introduction

Section snippets

Reagents

HM781-36B is a specific inhibitor of HER family kinases

Discussion

Conflicts of interest

Acknowledgements

Cell

Adv. Enzyme Regul.

Ann. Oncol.

Lancet

Cancer Lett.

Untangling the ErbB signalling network

Nat. Rev. Mol. Cell Biol.

Egf binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3

EMBO J.

Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model

Clin. Cancer Res.

Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin

Int. J. Oncol.

HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells

Cancer Res.

Breast cancer expressing the activated HER2/neu is sensitive to gefitinib in vitro and in vivo and acquires resistance through a novel point mutation in the HER2/neu

Cancer Res.

The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines

Cancer Lett.

Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells

Cancer Res.

Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells

Mol. Cancer Ther.

The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo

Mol. Cancer Ther.

Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2

PLoS ONE

EGFR mutation and resistance of non-small-cell lung cancer to gefitinib

New Engl. J. Med.

An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor

Cancer Res.

PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib

Cancer Res.

A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy

Cancer Res.

A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib

Cancer Res.