Investigation of fusion genes associated with ferroptosis resistance in cancer

Cancer is a complex disease characterized by loss of control of cellular growth caused by genetic abnormalities. Cancer treatment faces challenges such as drug resistance. Drug resistance refers to the condition in which cancer cells lose the ability to respond to treatment. Feroptosis is a molecular mechanism with potential to overcome the problem of drug resistance. Feroptosis is a type of programmed cell death mechanism characterized by iron-dependent accumulation of lipid peroxidases in cell membrane structures. Cancer cells that develop drug resistance may be rendered more sensitive to feroptosis, offering advantages in cancer treatment in favor of the patient. In addition to drug resistance, another abnormality seen in cancer cells is the formation of fusion transcripts caused by structural genetic changes. Fusion transcripts are RNA sequences resulting from abnormal splicing of genetic material. Fusion transcripts can help discover new drug targets in cancer treatment. The most successful molecular method used to discover fusion transcripts is RNA sequencing (RNAseq). RNAseq methods play an important role in creating customized treatment plans in cancer. In this study, we aimed to identify fusion transcripts associated with increased or decreased feroptosis resistance or sensitivity by analyzing RNAseq data of publicly available cancer cell lines. We found that a number of fusion genes exist, but not much is known about their functions and consequences. Some fusion genes have only been tested in clinical trials with a limited number of drugs. Therefore, we performed in-silico analyses using sensitivity data of specific drugs with the expression of genes associated with feroptosis pathways in cancer cell lines. As a result of these analyses, we collected valuable data for potential feroptosis-related gene-drug combinations that can be investigated in the future. In the light of the collected data, POR gene was positively correlated with gemcitabine, BCL2L1 gene with vinorelbine and NOX4 with docetaxel, vinorelbine and cisplatin. In contrast, RPL8 and VHL genes were negatively correlated with sorafenib, KEAP1 gene with Etoposide and BAP1 gene with cisplatin and gemcitabine. These correlations suggest that these genes may be potential therapeutic candidates against drugs. In addition, when we performed Log-Rank analyses using survival data from clinical datasets, we identified a large number of feroptosis genes associated with overall survival and disease-free survival.