Targeting ITGB4/SOX2-driven cancer stem cells using proteasome inhibitors

The transcription factor SOX2 required for pluripotency, is amplified in 40% of the lung squamous cell carcinoma (LUSC) cases. However, a long-term survival analysis using TCGA cohorts of LUSC patients revealed no significant differences between high versus low SOX2 expressing cases. The treatment options for irresectable LUSC are limited to chemotherapy where carboplatin or cisplatin is given in combination with gemcitabine. However, drug resistance remains a serious concern. We previously showed integrin β4 (ITGB4) and paxillin (PXN) play a critical role in platinum resistance in LUAD. Heterogenous NSCLC cells that up-regulate ITGB4 and PXN epigenetically, can switch phenotypes from cisplatin sensitive to tolerant. However, the significance of ITGB4 expression in SOX2 driven cancer stem cells (CSCs) in NSCLC remains unappreciated. In this study, we isolated CSCs from LUSC patients and characterized them. We elucidated the significance of ITGB4 and SOX2 expression in maintaining the stemness of CSCs and their response to cisplatin treatment. Finally, we showed that the proteasome inhibitor carfilzomib (CFZ) targets SOX2 dependent CSCs and this function of CFZ is independent of its proteasome inhibitory function. Triplicates are provided for Control, Actinomycin D, and Carfilzomib (CFZ) in 3 Cell Lines (H520, SBC5, and COH2) >>>Raw data for human samples not available due to either unknown consent or lack of explicit consent<<<