JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression

Autor:in

Mohrherr, Julian; Haber, Marcel; Breitenecker, Kristina; Aigner, Petra; Moritsch, Stefan; Voronin, Viktor; Eferl, Robert; Moriggl, Richard; Stoiber, Dagmar; Gyorffy, Balazs; Brcic, Luka; laszlo, viktoria; Doeme, Balazs; Moldvay, Judit; Dezso, Katalin; Bilban, Martin; Popper, Helmut; Moll, Herwig; Casanova, Emilio

Abstrakt

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.

Dokumententyp

Originalarbeit

Open Access Type

Hybrid

DOI

10.1002/ijc.32624

PubMed ID

MEDLINE:31407334