title: Adaptive Upregulation of EGFR Limits Attenuation of Tumor Growth by Neutralizing IL6 Antibodies, with Implications for Combined Therapy in Ovarian Cancer.
abstract: Excess production of the proinflammatory IL6 has both local and systemic tumor-promoting activity in many cancers, including ovarian cancer. However, treatment of advanced ovarian cancer patients with a neutralizing IL6 antibody yielded little efficacy in a previous phase II clinical trial. Here, we report results that may explain this outcome, based on the finding that neutralizing antibodies to IL6 and STAT3 inhibition are sufficient to upregulate the EGFR pathway in high-grade serous and other ovarian cancer cells. Cell treatment with the EGFR inhibitor gefitinib abolished upregulation of the EGFR pathway. Combining neutralizing IL6 antibodies and gefitinib inhibited malignant cell growth in 2D and 3D culture. We found that ErbB-1 was localized predominantly in the nucleus of ovarian cancer cells examined, contrasting with plasma membrane localization in lung cancer cells. Treatment with anti-IL6, gefitinib, or their combination all led to partial restoration of ErbB-1 on the plasma membrane. In vivo experiments confirmed the effects of IL6 inhibition on the EGFR pathway and the enhanced activity of a combination of anti-IL6 antibodies and gefitinib on malignant cell growth. Taken together, our results offer a preclinical rationale to combine anti-IL6 and gefitinib to treat patients with advanced stage ovarian cancer.
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors: Carla S
authors: CS
authors: Milagre
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors: Ganga
authors: G
authors: Gopinathan
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors: Gemma
authors: G
authors: Everitt
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors: Richard G
authors: RG
authors: Thompson
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors: Hagen
authors: H
authors: Kulbe
authors: MedImmune, One MedImmune Way, Gaithersburg, Maryland.
authors: Haihong
authors: H
authors: Zhong
authors: MedImmune, One MedImmune Way, Gaithersburg, Maryland.
authors: Robert E
authors: RE
authors: Hollingsworth
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
authors: Richard
authors: R
authors: Grose
authors: Cancer Genomics and Genetics Program, Peter MacCallum Cancer Centre, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors: David D L
authors: DD
authors: Bowtell
authors: UCL Cancer Institute, University College London, United Kingdom.
authors: Daniel
authors: D
authors: Hochhauser
authors: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom. f.balkwill@qmul.ac.uk.
authors: Frances R
authors: FR
authors: Balkwill
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002467:Cell Nucleus; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology; D020935:MAP Kinase Signaling System; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D021381:Protein Transport; D011799:Quinazolines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D066246:ErbB Receptors; D000077156:Gefitinib; D015850:Interleukin-6; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C494086:STAT3 protein, human; C512478:EGFR protein, human