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.

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.

• Authors: Hyun-Jin Nam, Keith A Ching, Julie Kan, Hwang-Phill Kim, Sae-Won Han, Seock-Ah Im, Tae-You Kim, James G Christensen, Do-Youn Oh, Yung-Jue Bang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 2 Pg. 439-51 (Feb 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22135232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolinones
• dacomitinib
• Receptor, ErbB-2
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Drug Synergism
• Female
• G1 Phase (drug effects)
• Humans
• Mice
• Mice, SCID
• Molecular Structure
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Quinazolinones (administration & dosage, chemistry, pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Time Factors
• Trastuzumab
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays