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

摘要: 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 has been reported. We investigated functional contribution other members family pathway NSCLC cells. In addition, we examined production these cytokines by cells cancer-associated fibroblasts (CAF). also analyzed prognostic significance molecule expressions clinical samples. with drugs, observed activation IL6-cytokine STAT3 along epithelial-to-mesenchymal transition (EMT) features. particular, oncostatin-M (OSM) induced switch EMT phenotype protected from drug-induced apoptosis OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The cross-talk CAFs preferentially activated OSM/STAT3 via paracrine mechanism decreased sensitivity drugs. selective JAK1 inhibitor filgotinib effectively suppressed OSMR expression, cotargeting inhibition oncogenic reversed analysis samples, gene expression appeared be associated worse prognosis surgically resected adenocarcinoma. Our data suggest that OSMRs/JAK1/STAT3 axis contributes cells, implying this could target. Mol Cancer Ther; 16(10); 2234-45. ©2017 AACR.