Leveraging drug-specific genes to identify sensitizers for resistant cancer cell lines

Therapeutic resistance remains a major obstacle in oncology, often arising from transcriptional reprogramming that enables cancer cells to escape drug-induced cytotoxicity. We aimed to develop a computational-experimental strategy to identify compounds capable of reversing resistance phenotypes. We integrated previously defined Drug-Specific Genes (DSGs), expression markers of drug sensitivity or resistance, with perturbational profiles from the Connectivity Map (CMap). Candidate compounds were prioritized based on their predicted ability to shift DSG expression toward a sensitized state. The top-ranked compound was validated in resistant HeLa and NCI-H1299 cell lines using BMS-345541 and Vorinostat as primary agents. Cell viability, apoptosis, and cell cycle progression were assessed. Chaetocin consistently emerged as a leading sensitizer in silico. Experimental validation confirmed that chaetocin enhanced the activity of BMS-345541 in HeLa cells and Vorinostat in NCI-H1299 cells. Combination treatments reduced cell viability, induced apoptosis, and promoted G2/M cell cycle arrest compared with primary drugs alone. DSG-guided transcriptional reversal offers a rational framework for overcoming therapeutic resistance. Our findings demonstrate that chaetocin can restore drug sensitivity in resistant cancer models, supporting its potential as a resistance-modulating agent in combination therapies. Given its epigenetic activity, chaetocin aligns with the emerging role of epigenetic modulators as promising partners in oncological co-treatments.