Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma

• Published in: Clinical cancer research Vol. 15; no. 10; pp. 3495 - 3502
• Main Authors: SCHICHER, Nikolaus, PAULITSCHKE, Verena, SWOBODA, Alexander, KUNSTFELD, Rainer, LOEWE, Robert, PILARSKI, Peter, PEHAMBERGER, Hubert, HOELLER, Christoph
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2009
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Cell Line; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Dermatology; Drug Synergism; EGFR; Erlotinib Hydrochloride; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; Immunoblotting; Immunohistochemistry; Ki-67 Antigen - analysis; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Medical sciences; melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, SCID; Pharmacology. Drug treatments; Platelet Endothelial Cell Adhesion Molecule-1 - analysis; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - administration & dosage; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; SCID mouse; Signal Transduction - drug effects; Tumor Burden - drug effects; Tumors of the skin and soft tissue. Premalignant lesions; VEGF; Xenograft Model Antitumor Assays; Antineoplastic agent; Enzyme; Tyrosine kinase inhibitor; Quinazoline derivatives; Transferases; Enzyme inhibitor; Monoclonal antibody; Malignant tumor; Biological activity; Bevacizumab; Vascular endothelium growth factor; Erlotinib; Malignant melanoma; Antiangiogenic agent; Protein-tyrosine kinase; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2407

Purpose: Melanoma is one of the most aggressive types of cancer with currently no chance of cure once the disease has spread to distant sites. Therapeutic options for advanced stage III and IV are very limited, mainly palliative, and show response in only ∼20% of all cases. The presented preclinical study was done to investigate the influence of a combined treatment of the epidermal growth factor receptor inhibitor erlotinib and the vascular endothelial growth factor monoclonal antibody bevacizumab in melanoma. Experimental Design and Results: The epidermal growth factor receptor was expressed in all cell lines tested, and treatment with erlotinib did inhibit the activation of the MEK/extracellular signal-regulated kinase and AKT signaling pathways. Whereas in vitro no influence on tumor cell proliferation was seen with erlotinib or bevacizumab monotherapy, a decreased invasive potential on erlotinib treatment in a three-dimensional Matrigel assay was observed. Furthermore, both drugs inhibited proliferation and sprouting of endothelial cells. In vivo , in a severe combined immunodeficient mouse xenotransplantation model, reduction in tumor volume under combined treatment with erlotinib and bevacizumab was superior to the additive effect of both single agents. This was associated with reduced cell proliferation, increased apoptosis, and a reduction in tumor angiogenesis compared with control or single treatment groups. Likewise, the reduction in the extent of lymph node and lung metastasis was most pronounced in animals treated with both drugs. Conclusion: The presented data strongly support the use of a combination of erlotinib and bevacizumab as a novel treatment regimen for metastatic melanoma.