In two novel reports entitled “MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC” and “A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in Lung cancer” published in the journal Proceedings of the National Academy of Sciences (PNAS), researchers uncover a mechanism underlying lung cancer cells’ resistance to current therapeutics.
TRAIL (short for TNF-related apoptosis-inducing ligand, a ligand that induces the process of cell death) is a promising anticancer agent in several cancers, however, an exception is lung cancer, particularly non-small cell lung cancer. Tumor cells are resistant to TRAIL anti-tumor activity but the mechanism behind this phenotype remained unknown to scientists.
In this new study, a team of researchers at The University of Manchester and colleagues at Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University discovered that lung cancer cells resistant to TRAIL carry a significant low expression of a particular microRNA (small noncoding RNAs that regulate gene expression), miR-148a, when compared to TRAIL-sensitive cells. The team discovered that upon forced expression miR-148a turned resistant TRAIL cells to become TRAIL sensitive. This resulted in a reduction of lung tumorigenesis, both in vitro and in vivo.
Dr. Michela Garofalo at the CRUK Manchester Institute and study co-lead author commented, “Discovering a potential reason why TRAIL is resisted by lung cancer could lead us to new treatments for this particularly deadly form of the disease. miR-148a certainly seems to play a role in this resistance, so it’s an avenue to explore alongside other factors which influence how the tumours respond to treatment.”
In the second published report, authors discovered another mechanism promoting tumours resistant to TRAIL. They found that TRAIL-resistant cells induce the expression of NF-κB. They suggest that combining NF-κB inhibitors and TRAIL is a potential effective therapy to increase lung cells susceptibility to TRAIL treatment.
Dr Garofalo added, “TRAIL is currently in clinical trials for other cancer types. But little is known about why non-small cell lung cancer is so resistant. These findings begin to shed light on those unique reasons, and suggest that by inhibiting the factors that cause resistance, TRAIL might become a useful treatment.”