Mechanisms of resistance to targeted therapies for uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Originating from melanocytes within the uveal tract, UM is associated with poor prognosis, chemoresistance, and high mortality, particularly in metastatic stages. Over 90% of UM cases exhibit mutually exclusive mutations in the GNAQ or GNA11 genes, which activate various signaling pathways,such as MAPK, PI3K, and YAP, through FAK. Conflicting research exists regarding the key signaling pathways and the resistance mechanisms proteins use to overcome inhibition through these pathways. These discrepancies underscore the need for a novel approach to clarify the significant signaling mechanisms and identify resistance mechanisms in UM. In this study, we address these issues by performing unbiased forward genetic approaches using the Sleeping Beauty (SB) mutagenesis system with targeted therapies to identify genetic drivers of resistance. The following chapters will explore how the SB-identified genes drive drug resistance, the mechanistic pathways they employ, and their relationship to cancer stem cells.