Disrupting SOX2 Self-Association and Condensates to Overcome Chemotherapeutic Drug Resistance in Lung Squamous Cell Carcinoma [RNA-Seq, 2]

Chemotherapy remains one of the most important treatments for lung squamous cell carcinoma (LSCC), yet overcoming chemotherapeutic drug resistance poses a significant challenge. The high frequency of SOX2 copy number amplification observed in LSCC patients underscores its potential role as a regulator in this context. Our investigation reveals a strong correlation between SOX2 amplification and expression levels in LSCC patients. Notably, overexpression of SOX2 confers resistance to chemotherapeutic drugs in LSCC cell lines. We elucidate that SOX2 undergoes phase separation, forming condensates that sequester chemotherapeutic agents used in LSCC treatment, thereby exacerbating chemotherapeutic drug resistance in LSCC cells. To address this, we design a small peptide containing 16 amino acids conjugated with 8 arginine, specifically targeting α-helix within HMG domain to disrupt SOX2 self-association. Our data demonstrate that this peptide effectively prevents SOX2 droplet formation, consequently reversing chemotherapy tolerance in LSCC without compromising SOX2 transcriptional activity. Collectively, our findings unveil a novel mechanism of chemotherapy resistance in LSCC mediated by SOX2 phase separation and propose a promising peptide-based therapeutic strategy to combat chemoresistance in LSCC.