Uveal melanoma (UM) is a rare form of melanoma that originates in the uveal tract of the eye and poses a significant clinical challenge due to its high likelihood of metastasis and the limited success of current systemic treatments, leading to a generally poor prognosis. One of the defining traits of UM is its exceptionally low tumor mutational burden compared to that seen in other melanoma subtypes and cancers. This low mutation rate limits the number of actionable genetic targets and contributes to the tumour’s inherent resistance to both immunotherapies and targeted treatments commonly used in advanced melanoma. These features indicate that epigenetic alterations may play a crucial role in the development, progression, and therapeutic resistance of UM.
Circular RNAs (circRNAs) are a recently identified group of non-coding RNAs that can act as epigenetic regulators in cancer development. They have potential utility in both biomarker development due to their tissue-specific expression and increased stability compared to their cognate linear, and also as therapeutic targets.
To investigate whether circRNAs may participate in driving treatment resistance to current and emerging therapies, we utilised UM cell lines that have been made resistant to PKC inhibitor (Darovasertib) and c-MET inhibitor (Crizotinib) and performed a long-read sequencing analysis (Oxford Nanopore Technologies) on RNA isolated from these cell lines to compare the expression of circRNAs. We identified a specific set of circRNAs that are associated PKC inhibitor resistance, and a distinct set that is associated with resistance to both PKC and c-MET inhibitors. Functional characterisation utilising the CRISPR Cas13d-mediated circRNA knock down is ongoing, and in vivo liver metastasis model will be used to establish physiological relevance. In addition, we have developed a highly sensitive digital PCR assay that allows the detection of these dysregulated circRNAs in plasma samples. Findings from this work are expected to lead to the development of an accurate early detection biomarker, and novel circRNA therapeutic targets that can effectively treat metastatic UM.