Abstract
Currently, there is no effective treatment for metastatic uveal melanoma (UVM). Here, we aimed to identify the mechanism involving intrinsic chemoresistance of metastatic UVM and the relevant therapeutic targets for UVM. We analyzed cohorts of 80 and 67 patients with primary UVM and skin cutaneous melanoma (SKCM), respectively, using The Cancer Genome Atlas dataset. Mutational burdens identified by whole exome sequencing were significantly lower in UVM than in SKCM patients. COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair. Transcriptome analysis revealed that the MYC signature was more enriched in UVM patients, as compared to SKCM patients. Fifty-nine (73.8%) of 80 UVM patients showed gains in MYC copy number, and a high MYC copy number was associated with aggressive clinicopathological features of tumors and poor survival. Kinome-wide siRNA library screening identified several therapeutic targets, reported as synthetic lethal targets for MYC-addicted cancers. Notably, UVM cell lines showed high susceptibility to a WEE1 inhibitor (MK-1775; adavosertib) at a clinically tolerable dose. Overall, our study identified high MYC activity in UVM, and suggested G2/M checkpoint inhibitors as effective therapeutic targets for UVM.
Highlights
Uveal melanoma (UVM) and skin cutaneous melanoma (SKCM) are both derived from melanocytes but show different characteristics, including significant differences in tumorigenesis, genetic alterations, and therapeutic responses[1]
There were no significant differences in age and sex between the uveal melanoma (UVM) and SKCM groups
Mutant GNAQ/ GNA11-induced activation of the MAPK and Hippo-YAP pathways has been reported in many basic and translational studies, and has suggested as essential for tumorigenesis of UVM7,16. These studies have not led to an improvement in clinical outcomes of UVM patients
Summary
Uveal melanoma (UVM) and skin cutaneous melanoma (SKCM) are both derived from melanocytes but show different characteristics, including significant differences in tumorigenesis, genetic alterations, and therapeutic responses[1]. The BRAF V600E mutation commonly seen in SKCM patients is not frequently observed in UVM patients, and GNAQ/GNA11, SF3B1, EIF1AX, and BAP1 mutations seen in UVM patients are rarely observed in SKCM patients[2,3]. Vemurafenib, a targeted agent for BRAF V600E, significantly improves therapeutic outcomes in SKCM patients[4]. The GNAQ/GNA11 mutations frequently observed in UVM patients have been reported to activate the MAPK pathway, but clinical trials with the MEK1/2 inhibitor, selumetinib, have failed to improve survival[5,6,7]. The difference in therapeutic outcomes between the two tumors has been further verified by the recent introduction of immune checkpoint inhibitors. Immunotherapy has led to favorable therapeutic outcomes for SKCM patients[8]. Some studies have reported the response to immune checkpoint inhibitors in UVM, but the effect was limited to minority of UVM9–12. We analyzed the whole exome sequencing and transcriptome (mRNA) sequencing data of UVMs and SKCMs in The Cancer Genome Atlas (TCGA) dataset, and performed kinome-wide siRNA library screening to characterize UVM and to identify potential therapeutic targets of UVM
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