journal contribution
posted on 2023-04-03, 15:50 authored by Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Carmen Behrens, Li Shen, Neda Kalhor, Juhee Song, J. Jack Lee, Jing Wang, Ximing Tang, Roy S. Herbst, Shinichi Toyooka, Luc Girard, John D. Minna, Jonathan M. Kurie, Ignacio I. Wistuba, Julie G. Izzo <p>Figure S3. Activated pathway analysis after proinflammatory cytokine stimulation in NSCLC cells. H23 cells were transfected with an siRNA specific for IL6 cytokine receptors (OSMR, LIFR), JAK family members, or scrambled negative control for 72 hours and then were treated with an IL6 family-cytokine (rhIL6, rhOSM, rhLIF; 1 ng.mL) for 1 hour. Expression levels of indicated proteins in cell lysates were analyzed by Western blotting. Sufficient knockdown efficacy by each siRNA was confirmed. When JAK1 was knocked down, expression of OSMR was also downregulated.</p>
Funding
NIH NCI grants
UT Lung Specialized Programs of Research Excellence
MD Anderson's Institutional Tissue Bank (ITB)
Japan Society for the Promotion of Science
History
ARTICLE 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.
