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JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression
Author(s) -
Mohrherr Julian,
Haber Marcel,
Breitenecker Kristina,
Aigner Petra,
Moritsch Stefan,
Voronin Viktor,
Eferl Robert,
Moriggl Richard,
Stoiber Dagmar,
Győrffy Balázs,
Brcic Luka,
László Viktória,
Döme Balázs,
Moldvay Judit,
Dezső Katalin,
Bilban Martin,
Popper Helmut,
Moll Herwig P.,
Casanova Emilio
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32624
Subject(s) - cancer research , ruxolitinib , jak stat signaling pathway , carcinogenesis , stat , signal transduction , lung cancer , janus kinase , chemokine , adenocarcinoma , tumor microenvironment , tumor progression , medicine , tyrosine kinase , biology , inflammation , stat3 , immunology , cancer , cytokine , myelofibrosis , microbiology and biotechnology , bone marrow , tumor cells
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.