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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Mohrherr, J; Haber, M; Breitenecker, K; Aigner, P; Moritsch, S; Voronin, V; Eferl, R; Moriggl, R; Stoiber, D; Győrffy, B; Brcic, L; László, V; Döme, B; Moldvay, J; Dezső, K; Bilban, M; Popper, H; Moll, HP; Casanova, E.
JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression.
Int J Cancer. 2019; 145(12):3376-3388
Doi: 10.1002/ijc.32624
[OPEN ACCESS]
Web of Science
PubMed
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- Co-authors Med Uni Graz
- Brcic Luka
- Popper Helmuth
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- Abstract:
- 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. © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
- Find related publications in this database (Keywords)
- non-small cell lung cancer
- lung adenocarcinoma (AC)
- Kirsten rat sarcoma viral proto-oncogene (K-RAS)
- Janus kinase (JAK)
- ruxolitinib
- cell-line derived xenografts
- genetically engineered mouse models
- tumor microenvironment (TME)
- tumor promoting inflammation