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Mol Cancer Ther. 2017 Oct;16(10):2234-2245. doi: 10.1158/1535-7163.MCT-17-0148. Epub 2017 Jul 20.

JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer.

Author information

1
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
7
Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan.
8
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas.
9
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. iiwistuba@mdanderson.org jizzo@mdanderson.org.

Abstract

Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234-45. ©2017 AACR.

PMID:
28729401
PMCID:
PMC5628136
DOI:
10.1158/1535-7163.MCT-17-0148
[Indexed for MEDLINE]
Free PMC Article

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