THERAPY RESISTANCE IN MELANOMA DRIVES CILIOGENESIS AND GLUTAMINE/ASPARTATE METABOLISM DEPENDENCY

Despite the remarkable success of new therapeutic approaches, a considerable number of melanoma patients still relapse on conventional therapies within two years and develop resistance. Alterations in metabolism, including amino acid availability and regulation of metabolic processes, have been implicated in acquired drug resistance. In this study, we developed in vitro and in vivo models of target therapy resistance (TTR) and identified a translational program that supports primary ciliogenesis in drug-resistant BRAF melanoma. We established that drug resistance enhances primary ciliogenesis, which is needed to respond and survive to combination therapy (CT). Mechanistically, impairing cilia formation (IFT88KO) rewires glutamine and aspartate metabolism. Overall, we provide a new molecular mechanism underlying therapy resistance that should be considered to tailored therapeutic strategies.