Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.

Abstract

The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.

• Authors: Michael A Morse, Junping Wei, Zachary Hartman, Wenle Xia, Xiu-Rong Ren, Gangjun Lei, William T Barry, Takuya Osada, Amy C Hobeika, Sharon Peplinski, Haixiang Jiang, Gayathri R Devi, Wei Chen, Neil Spector, Andrea Amalfitano, H Kim Lyerly, Timothy M Clay
• Journal: International journal of cancer (Int J Cancer) Vol. 126 Issue 12 Pg. 2893-903 (Jun 15 2010) ISSN: 1097-0215 [Electronic] United States
• PMID: 19856307 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cancer Vaccines
• Protein Kinase Inhibitors
• Quinazolines
• RNA, Messenger
• Lapatinib
• Receptor, ErbB-2

Topics

• Adenoviridae (genetics)
• Animals
• Blotting, Western
• Breast Neoplasms (immunology, metabolism, therapy)
• Cancer Vaccines (therapeutic use)
• Cell Proliferation
• Combined Modality Therapy
• Drug Synergism
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Genetic Therapy
• Humans
• Lapatinib
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays