Abstract 7574: Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC

Abstract This study addresses the current lack of small molecules targeting SOX2, a pivotal protein in cancer, through an examination of the effectiveness of FDA-approved drugs and proteasome inhibitors. Building on prior research demonstrating the proteasome inhibitor CFZ's capacity to diminish the expression of ITGB4 and PXN in LUAD effectively, our investigation highlights CFZ and IXA as potent inhibitors at nanomolar concentrations. Notably, CFZ treatment enhances sensitivity to cisplatin by suppressing the expression of ITGB4 and the stemness-associated gene SOX2.At a mechanistic level, CFZ hinders histone acetylation at the SOX2 promoter site, leading to rapid and specific downregulation. RNA-seq analysis of COH2 cells treated with CFZ unveils substantial downregulation of genes related to transcription and DNA binding. Z score analysis further reveals a noteworthy inhibition of key transcription factors (TFs), including SOX2, NANOG, POU5F1, SALL4, and KLF4. This TF inhibition extends to neuroendocrine cell lines, identifying 16 overlapping targets of SOX2 associated with stemness. These findings suggest a potential therapeutic approach for targeting cisplatin-resistant cancer stem cells across various cancer types. Moreover, the study proposes a synergistic effect of cisplatin and CFZ in mitigating the growth of neuroendocrine phenotype, SCLC. Given the limited medical options currently available for this phenotype, this insight holds particular significance. In conclusion, our study unveils CFZ as a potent transcriptional suppressor of SOX2, providing a novel strategy to sensitize cisplatin-resistant cancer stem cells. The results underscore the interplay of genetic and non-genetic mechanisms in drug resistance, emphasizing the significance of repurposing drugs for other indications. Citation Format: Atish Mohanty, Linlin Guo, Sravani Ramisetty, Sharad Singhal, Erminia Massarelli, Prakash Kulkarni, Ravi Salgia. Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7574.