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Multi-Platform Omics Analysis for Identification of Molecular Characteristics and Therapeutic Targets of Uveal
Yong Joon Kim1, Seo Jin Park1, Kyung Joo Maeng1
1Department of Ophthalmology, Institute of Vision Research, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
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.
Insights
Metastatic uveal melanoma (UVM) lacks effective treatments. This study reveals high MYC activity in UVM, identifying WEE1 inhibitors as promising therapeutic targets for this rare cancer.
Area of Science:
- Oncology
- Genomics
- Melanoma Research
Background:
- Metastatic uveal melanoma (UVM) presents a significant unmet clinical need due to a lack of effective treatments.
- Understanding the molecular mechanisms of intrinsic chemoresistance in UVM is crucial for developing targeted therapies.
Purpose of the Study:
- To identify the underlying mechanisms of chemoresistance in metastatic UVM.
- To discover novel therapeutic targets for UVM treatment.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) dataset for UVM and skin cutaneous melanoma (SKCM) cohorts.
- Whole exome sequencing and COSMIC mutational signature analysis.
- Transcriptome analysis, copy number variation analysis, and kinome-wide siRNA library screening.
Main Results:
- UVM patients exhibited lower mutational burdens compared to SKCM patients, with mutations primarily linked to 5-methylcytosine deamination or mismatch repair deficiency.
- A significantly enriched MYC signature and high MYC copy number gains (73.8%) were observed in UVM, correlating with aggressive features and poor survival.
- UVM cell lines demonstrated high susceptibility to the WEE1 inhibitor adavosertib (MK-1775) at a clinically tolerable dose.
Conclusions:
- High MYC activity is a key feature of UVM, contributing to its aggressive nature and chemoresistance.
- G2/M checkpoint inhibitors, such as WEE1 inhibitors, represent promising therapeutic strategies for metastatic uveal melanoma.
