Abstract
The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK inhibitor-resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK inhibitor-resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease.
Highlights
Uveal melanoma accounts for approximately 5% of all melanomas
The RAS/RAF/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules, such as RAS and BRAF in cutaneous melanoma, and GNAQ/11 in uveal melanoma [4, 5]
We found that in uveal melanoma cell lines, the sustained inhibition of MEK leads to increased expression of DDX43, and consequent induction of RAS and downstream pathways
Summary
Uveal melanoma accounts for approximately 5% of all melanomas. Most arise from melanocytes within the uveal tract, which consists of the iris, ciliary body, and choroid of the eye [1]. This type of melanoma has a very high tendency to metastasize to the liver [2]. As opposed to cutaneus melanoma, BRAF and RAS mutations are absent or extremely rare in uveal melanoma [3]. Most patients with uveal melanoma die due to metastatic disease and there are limited therapeutic options [9, 10].
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