Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.
Jose M VicencioR EvansR GreenZ AnJ DengC TreacyR MustaphaJ MonypennyC CostoyaK LawlerK NgK De-SouzaO CobanValentí GómezJ ClancyS H ChenA ChalkF WongP GordonC SavageC GomesT PanG AlfanoL DolcettiJ N E ChanF Flores-BorjaP R BarberG WeitsmanD SosnowskaE CaponeS IacobelliD HochhauserJ A HartleyMaddy ParsonsJ N ArnoldSimon M Ameer-BegSergio A QuezadaYosef YardenGianluca SalaTony T NgPublished in: Cell death & disease (2022)
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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