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Gewählte Publikation:

[Article in Press]

Publikationstyp: Zeitschriftenaufsatz
Dokumentart: Originalarbeit

Publikationsjahr: 2019

AutorInnen: 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

Titel: JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression.

Quelle: Int J Cancer. 2019;



Autor/innen der Vetmeduni Vienna:

Moriggl Richard

Beteiligte Vetmed-Organisationseinheiten
Abteilung für Funktionelle Krebsgenomik


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 (TKI) 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 anti-tumorigenic tumor microenvironment (TME), characterized by decreased levels of tumor-promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells (MDSCs), thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K-RAS-driven lung AC. This article is protected by copyright. All rights reserved.


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