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

Cell Death Dis. 2022 Mar 28;13(3):274. doi: 10.1038/s41419-022-04701-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Acrylamides
  • Aniline Compounds
  • Antibodies, Monoclonal
  • Protein Kinase Inhibitors
  • osimertinib
  • ErbB Receptors
  • Protein Serine-Threonine Kinases
  • Nucleotidyltransferases
  • Endoribonucleases