Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Jose Vicencio Bustamante*, Rachel Evans, R Green, Z An, Jinhai Deng, Conor Treacy, Rami Mustapha, James Monypenny of Pitmilly, C Costoya , K Lawler, K Ng, Karen Desouza, O Coban, V Gomez, J Clancy, SH Chen, A Chalk, F Wong, P Gordon, Courtney SavageC Gomes, T Pan, Giovanna Alfano, Luigi Dolcetti, Julie Nuo En Chan, F Florez-Borja , Paul Barber, Gregory Weitsman, D Sosnowska, E Capone, S Iacobelli, D Hochhauser, J Hartley, Madeline Parsons, James Arnold, Simon Ameer-Beg, Sergio A Quezada, Yosef Yarden, G Sala, Tony Ng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
106 Downloads (Pure)

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.

Original languageEnglish
Article number274
JournalCell Death & Disease
Volume13
Issue number3
Early online date28 Mar 2022
DOIs
Publication statusPublished - 28 Mar 2022

Keywords

  • Acrylamides
  • Aniline Compounds/pharmacology
  • Animals
  • Antibodies, Monoclonal/pharmacology
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Endoribonucleases
  • ErbB Receptors/genetics
  • Humans
  • Lung Neoplasms/drug therapy
  • Mice
  • Mutation
  • Neoplasm Recurrence, Local/drug therapy
  • Nucleotidyltransferases
  • Protein Kinase Inhibitors/pharmacology
  • Protein Serine-Threonine Kinases

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