Abstract by Christoffer Lynge Halvorsen

The onset of drug resistance is one of the largest challenges in current cancer treatment. This is especially the case in treatment of NSCLC where virtually all cases either already are resistant or will eventually become resistant to standard-of-care platinum-based chemotherapy. In this study we generated cisplatin resistant NSCLC cell lines and performed cell cycle-based RNA sequencing to explore cell cycle specific expression differences. While most studies focus on the immediate effect of cisplatin on DNA damage and cell cycle, this study seeks to explore the long-term changes cells acquire when treated with cisplatin for a prolonged time. Transcriptomic data indicated that cisplatin-resistant cells did not upregulate MDR genes, did not increase expression of DNA damage repair factors, but had a major downregulation in known cancer stem cell markers, pointing to a more differentiated phenotype. We additionally observed that specifically G1 and S-phase fractions in resistant cells have a significant upregulation of negative regulation of hydrolases and peptidases, potentially increasing protein stability in cisplatin-resistant cells. Despite the large heterogeneity between NSCLC cell lines, we were able to identify CST1, an overall upregulated gene in all cell lines, and B3GALT5, specifically upregulated in G1 in all cell lines, as clinically relevant biomarkers of cisplatin resistance. These results indicate an unconventional resistance phenotype of increased differentiation and overall slower cell cycle, leading to increased resistance towards cisplatin treatment.