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Publication Detail
Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans
  • Publication Type:
    Journal article
  • Authors:
    Vicencio JM, Evans R, Green R, An Z, Deng J, Treacy C, Mustapha R, Monypenny J, Costoya C, Lawler K, Ng K, De-Souza K, Coban O, Gomez V, Clancy J, Chen SH, Chalk A, Wong F, Gordon P, Savage C, Gomes C, Pan T, Alfano G, Dolcetti L, Chan JNE, Flores-Borja F, Barber PR, Weitsman G, Sosnowska D, Capone E, Iacobelli S, Hochhauser D, Hartley JA, Parsons M, Arnold JN, Ameer-Beg S, Quezada SA, Yarden Y, Sala G, Ng T
  • Publisher:
    Springer Science and Business Media LLC
  • Publication date:
    28/03/2022
  • Journal:
    Cell Death & Disease
  • Volume:
    13
  • Issue:
    3
  • Article number:
    274
  • Medium:
    Electronic
  • Status:
    Published
  • Country:
    England
  • PII:
    10.1038/s41419-022-04701-3
  • Language:
    English
  • Keywords:
    Experimental models of disease, Growth factor signalling, Non-small-cell lung cancer, Preclinical research, Prognostic markers
  • Notes:
    Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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.
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