A research team led by Dr. Tackhoon Kim at the Center for Medicinal Materials Research at the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh) has identified a new key mechanism behind the resistance of melanoma to BRAF inhibitors and has proposed a strategy to develop new anticancer therapies to overcome this resistance.
The research team used melanoma cell line models resistant to BRAF inhibitors and discovered that the activation of the AMD1 gene plays a crucial role in the development of drug resistance. The AMD1 gene is essential for polyamine biosynthesis, which promotes cell growth and proliferation. It was found that polyamine levels are generally higher in BRAF inhibitor resistant cancer cells. Through experiments, the team confirmed that inhibiting polyamine biosynthesis lowers resistance to BRAF inhibitors, leading to melanoma cell death.
Furthermore, the study revealed that the oncogene c-Myc triggers the increase of polyamine biosynthesis in BRAF-resistant melanoma. This increase in polyamines enhances mitochondrial protein levels, boosting mitochondrial activity and contributing to the proliferation of cancer cells resistant to treatment. The researchers identified this process as the core mechanism driving BRAF inhibitor resistance in melanoma. This is the first study in the world to pinpoint polyamine biosynthesis as a cause of BRAF inhibitor resistance. The KIST team also suggested an anticancer drug development strategy to block each stage of the resistance mechanism.
This research opens the door to developing new anticancer therapies based on regulating polyamine metabolism, which could be used to treat melanoma, a cancer that has been difficult to cure due to frequent drug resistance.
National Research Council of Science and Technology release on Newswise
