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Mol Cancer Ther. 2012 Feb;11(2):439-51. doi: 10.1158/1535-7163.MCT-11-0494. Epub 2011 Dec 1.

Evaluation of the antitumor effects and mechanisms of PF00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer.

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1
Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Jongno-gu, Seoul, 110-744, Korea.

Abstract

Recently, HER2-directed treatment, such as trastuzumab, has shown clinical benefit in HER2-amplified gastric cancer. On the basis of recent studies about epidermal growth factor receptor (EGFR) or HER2-targeting agents (including gefitinib, lapatinib, and trastuzumab) in gastric cancer, the potent effects of pan-HER inhibitors targeting the HER family are anticipated. In this study, we evaluated the activity and mechanisms of PF00299804, an irreversible pan-HER inhibitor, in gastric cancer in vitro and in vivo models. PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF00299804 induced apoptosis and G(1) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF00299804 also blocked EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular-targeted agents including trastuzumab (an anti-HER2 monoclonal antibody), CP751871 (an IGF1R inhibitor), PD0325901 (an ERK1/2 inhibitor), and PF04691502 (a PI3K/mTOR inhibitor) produced synergistic effects. These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of HER2-amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and/or molecular-targeted agents.

PMID:
22135232
DOI:
10.1158/1535-7163.MCT-11-0494
[Indexed for MEDLINE]
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