MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Cell Cycle Checkpoints
/ drug effects
Cell Death
/ drug effects
Cell Line, Tumor
Cytokines
/ metabolism
DEAD Box Protein 58
/ metabolism
ErbB Receptors
/ metabolism
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Immune Evasion
/ drug effects
Immunity, Innate
/ drug effects
Inflammation
/ pathology
Interferon Regulatory Factor-1
/ metabolism
MAP Kinase Signaling System
/ drug effects
Mice
Mice, Inbred C57BL
Neoplasms
/ metabolism
Oncogenes
Protein Kinase Inhibitors
/ pharmacology
Receptors, Immunologic
/ metabolism
Signal Transduction
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 09 2021
17 09 2021
Historique:
received:
25
11
2020
accepted:
23
08
2021
entrez:
18
9
2021
pubmed:
19
9
2021
medline:
13
10
2021
Statut:
epublish
Résumé
Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8
Identifiants
pubmed: 34535668
doi: 10.1038/s41467-021-25728-8
pii: 10.1038/s41467-021-25728-8
pmc: PMC8448826
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cytokines
0
IRF1 protein, human
0
Interferon Regulatory Factor-1
0
MAVS protein, human
0
Protein Kinase Inhibitors
0
Receptors, Immunologic
0
ErbB Receptors
EC 2.7.10.1
RIGI protein, human
EC 3.6.1.-
DEAD Box Protein 58
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5505Subventions
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Informations de copyright
© 2021. The Author(s).
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