학술논문
Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.
Document Type
Academic Journal
Author
Vicencio JM; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK. j.vicencio@ucl.ac.uk.; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK. j.vicencio@ucl.ac.uk.; Evans R; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Green R; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; An Z; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Deng J; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Treacy C; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Mustapha R; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Monypenny J; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Costoya C; Cancer Immunology Unit, Cancer Institute, University College London, London, UK.; Lawler K; Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.; Ng K; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; De-Souza K; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Coban O; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Gomez V; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Clancy J; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Chen SH; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Chalk A; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Wong F; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Gordon P; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Savage C; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Gomes C; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Pan T; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Alfano G; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Dolcetti L; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Chan JNE; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Flores-Borja F; Centre for Immunobiology and Regenerative Medicine, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Barber PR; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Weitsman G; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Sosnowska D; School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Capone E; Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Center for Advanced Studies and Technology (CAST), Chieti, Italy.; Iacobelli S; MediaPharma SRL, Chieti, Italy.; Hochhauser D; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Hartley JA; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK.; Parsons M; Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK.; Arnold JN; School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Ameer-Beg S; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.; Quezada SA; Cancer Immunology Unit, Cancer Institute, University College London, London, UK.; Yarden Y; Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.; Sala G; Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Center for Advanced Studies and Technology (CAST), Chieti, Italy.; Ng T; Molecular Oncology Group, Cancer Institute, Paul O'Gorman Building, University College London, London, UK. tony.ng@kcl.ac.uk.; Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK. tony.ng@kcl.ac.uk.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
Subject
Language
English
Abstract
Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.
(© 2022. The Author(s).)
(© 2022. The Author(s).)