Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.
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
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
28 03 2022
28 03 2022
Historique:
received:
11
11
2021
accepted:
01
03
2022
revised:
07
02
2022
entrez:
29
3
2022
pubmed:
30
3
2022
medline:
15
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35347108
doi: 10.1038/s41419-022-04701-3
pii: 10.1038/s41419-022-04701-3
pmc: PMC8960767
doi:
Substances chimiques
Acrylamides
0
Aniline Compounds
0
Antibodies, Monoclonal
0
Protein Kinase Inhibitors
0
osimertinib
3C06JJ0Z2O
ErbB Receptors
EC 2.7.10.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Nucleotidyltransferases
EC 2.7.7.-
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
274Subventions
Organisme : Cancer Research UK (CRUK)
ID : 176885
Organisme : Cancer Research UK (CRUK)
ID : C7675/A29313
Organisme : Cancer Research UK (CRUK)
ID : C604/A27442
Organisme : Cancer Research UK (CRUK)
ID : DCRPGF\100009
Organisme : Cancer Research UK (CRUK)
ID : C7893/A26233
Organisme : Cancer Research UK (CRUK)
ID : C1519/A16463
Organisme : Cancer Research UK (CRUK)
ID : C604/A25135
Organisme : Cancer Research UK (CRUK)
ID : C1519/A27375
Organisme : Cancer Research UK (CRUK)
ID : C1519/A28682
Informations de copyright
© 2022. The Author(s).
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