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

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.

Label-free nanoscale mapping of intracellular organelle chemistry

“…We believe that this capacity for quantitative intracellular imaging offers significant potential for the discovery of nanoscale biomarkers of disease 34 , as well as characterising the efficacy and operating mechanisms of a wide range of therapeutics, in particular drugs such as bortezomib and osimertinib 35 , which generally have distinct chemical signatures that can be exploited with s-SNOM. We note that s-SNOM imaging should be suitable for samples that have been prepared for correlative light and electron microscopy 36 , in particular resin-embedding and cryosectioning approaches.…”

The proto-oncogene c-Src phosphorylates cGAS to reduce DNA binding and activation

“…In support of this, oncogenic MYC signaling has been shown to induce epigenetic silencing of cGAS-STING signaling in triple-negative breast cancer 69 . Similarly, the HER2 (ERBB2) pathway disrupts STING signaling through AKT mediated phosphorylation and dysregulation of TBK1, while combination targeted therapy with the tyrosine kinase inhibitor Osimertinib and monoclonal antibodies targeting HER3 was recently shown to induce enhanced tumor cell cGAMP production and paracrine STING activation in tumor-associated macrophages to facilitate tumor clearance 33,70 . Thus, a more detailed understanding of cancer subtype specific strategies of immune evasion will enable the generation of rationally designed combination therapies aimed at restoring tumor immunogenicity.…”

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

“…[60] Tyrosinase inhibitor (e.g., osimertinib, anlotinib) leads to tumor cell apoptosis, increases macrophage infiltration via inositol-requiring-enzyme (IRE1𝛼)dependent HER3 up-regulation, and activates cGAS in cancer cells to generate cGAMP, which is transported to macrophages followed by STING activation. [61] Protease inhibitor (e. g., bortezomib, BTZ) induces genomic instability and inhibits DNA repair, resulting in accumulation of the cytosolic DNA sensor cGAS and activation of STING pathway. [62] ATR and topoisomerase 1 (TOP1) inhibitor activates the STING pathway by micronuclei.…”