Abstract 745: Oncostatin M receptor activation leads to molecular targeted therapy resistance in non-small cell lung cancer

Background: The emergence of molecular targeted therapies against driver mutations and gene fusions has resulted in significant therapeutic advances within a subset of non-small cell lung cancer (NSCLC) patients. However, even when targeted therapy is effective, patients eventually develop resistance and better therapies in this setting are still being sought. Preliminary studies, from the ongoing BATTLE-2 clinical trial in chemo-refractory NSCLC, identified a number of molecular candidates portending to targeted therapy resistance, including the oncostatin M (OSM) and leukemia inhibitory factor (LIF) receptors (OSMR, LIFR), both co-localized on a frequently amplified chromosome 5p region. In this study, we investigated the functional contribution of the OSM pathway to targeted therapy resistance in NSCLC. Materials and Methods: We analyzed OSM, OSMR, LIFR, and associated downstream pathways in a panel of OSMR-LIFR amplified (10) and diploid (10) NSCLC cell lines, in both mono- and co-culture experiments using human normal and lung cancer-associated fibroblasts (CAFs). We assessed the effect of OSM pathway stimulation and blockade on sensitivity to a variety of molecularly targeted agents. Further, we performed correlative studies using the BATTLE-2 molecular dataset. Results: OSM stimulation activated cell proliferation and survival pathways (AKT-mediated) through OSMR and LIFR. In addition, a dramatic JAK1/STAT3 pathway activation was predominant in OSMR amplified cells and was associated with EMT features. Co-culture experiments suggested a preferential paracrine activation of the OSM-STAT3 pathway, underscoring the importance of the microenvironment. Interestingly, OSM stimulation protected cells from drug-induced apoptosis in a STAT3-dependent manner. In the BATTLE-2 translational analysis, we also found that OSMR upregulation was significantly associated to STAT3 upregulation and EMT-gene expression signatures. Conclusions: Our data suggest that the OSM-OSMR/LIFR-STAT3 pathway causes EMT and contributes to molecular targeted therapy resistance in oncogene-addicted NSCLC cells, suggesting that this pathway could be a therapeutic target in NSCLC. Ongoing experiments are assessing therapeutic vulnerabilities and refining the signaling functionally involved. Supported by NIH-NCI CA155196 & 2P50CA070907-16A1 Citation Format: Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Nana E. Hanson, Neda Kalhor, J. Jack Lee, Waun Ki Hong, Ximing Tang,