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Int J Cancer. 2019 Aug 12. doi: 10.1002/ijc.32624. [Epub ahead of print]

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

Author information

1
Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
2
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
3
Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
4
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
5
Medical University of Vienna, Vienna, Austria.
6
MTA TK Lendület Cancer Biomarker Research Group, Institute of Enzymology HU-1117, and Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
7
Diagnostic & Research Institute of Pathology, Medical University of Graz, Austria.
8
Division of Thoracic Surgery, Department of Surgery & Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
9
Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular, and Gender Imaging, Medical University of Vienna, Vienna, Austria.
10
Department of Tumor Biology, National Korányi Institute of Pulmonology, Semmelweis University, Budapest, Hungary.
11
Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary.
12
SE-NAP Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
13
First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
14
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
15
Core Facilities, Medical University of Vienna, Vienna, Austria.

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.

KEYWORDS:

Cell-line derived xenografts; Genetically engineered mouse models (GEMMs); Janus kinase (JAK); Kirsten Rat Sarcoma Viral Proto-Oncogene (K-RAS); Lung adenocarcinoma (AC); Non-small cell lung cancer (NSCLC); Ruxolitinib; Tumor microenvironment (TME); Tumor promoting inflammation

PMID:
31407334
DOI:
10.1002/ijc.32624

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