Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors
Linlin Guo, Atish Mohanty, Sharad S. Singhal, Saumya Srivastava, Arin Nam, Charles Warden, Sravani Ramisetty, Yate‐Ching Yuan, Hyejin Cho, Xiwei Wu, Aimin Li, Manik Vohra, Srinivas Vinod Saladi, Deric L. Wheeler, Leonidas Arvanitis, Erminia Massarelli, Prakash Kulkarni, Yiming Zeng, Ravi Salgia
Abstract
This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo . The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.