JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression.
A549 Cells
Adenocarcinoma of Lung
/ drug therapy
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Disease Progression
Humans
Janus Kinase Inhibitors
/ pharmacology
Janus Kinases
/ antagonists & inhibitors
Lung Neoplasms
/ drug therapy
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Proto-Oncogene Mas
Proto-Oncogene Proteins p21(ras)
/ metabolism
STAT Transcription Factors
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Tumor Microenvironment
/ drug effects
Janus kinase (JAK)
Kirsten rat sarcoma viral proto-oncogene (K-RAS)
cell-line derived xenografts
genetically engineered mouse models
lung adenocarcinoma (AC)
non-small cell lung cancer
ruxolitinib
tumor microenvironment (TME)
tumor promoting inflammation
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
19
02
2019
revised:
11
07
2019
accepted:
22
07
2019
pubmed:
14
8
2019
medline:
31
1
2020
entrez:
14
8
2019
Statut:
ppublish
Résumé
Oncogenic K-RAS has been difficult to target and currently there is no K-RAS-based targeted therapy available for patients suffering from K-RAS-driven lung adenocarcinoma (AC). Alternatively, targeting K-RAS-downstream effectors, K-RAS-cooperating signaling pathways or cancer hallmarks, such as tumor-promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK-STAT pathway is considered to be a central player in inflammation-mediated tumorigenesis, we investigated here the implication of JAK-STAT signaling and the therapeutic potential of JAK1/2 inhibition in K-RAS-driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK-STAT signaling correlated with disease progression and K-RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K-RAS-driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor-promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K-RAS-driven lung AC.
Identifiants
pubmed: 31407334
doi: 10.1002/ijc.32624
pmc: PMC6856680
doi:
Substances chimiques
Antineoplastic Agents
0
Janus Kinase Inhibitors
0
KRAS protein, human
0
MAS1 protein, human
0
Proto-Oncogene Mas
0
STAT Transcription Factors
0
Janus Kinases
EC 2.7.10.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3376-3388Informations de copyright
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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