Uveal melanoma is the most common primary intraocular tumor in adults and carries a very poor prognosis. Although the primary lesion can be effectively treated with proton therapy or enucleation, up to half of patients develop metastases, most often in the liver. These metastatic forms are resistant to all existing treatments: ninety percent of affected patients die within six months of the diagnosis of metastasis. A recent bispecific immunotherapy, tebentafusp, improves overall survival, but its benefit is limited to patients carrying the HLA-A*02:01 haplotype and applies to only a small proportion of them. Identifying new oncogenic mechanisms and therapeutic targets independent of HLA status therefore addresses an unmet clinical need. The main oncogenic drivers of this disease, GNAQ or GNA11 mutations and their downstream signaling pathways, have so far not led to effective clinical strategies.
To uncover exploitable vulnerabilities, the authors carried out a CRISPR-Cas9 loss-of-function screen based on a library of chromatin regulators. This approach identified the lysine methyltransferase SETDB1 as a critical player in the proliferation and survival of metastatic uveal melanoma cells. Functionally, SETDB1 deficiency triggers a DNA damage response, a senescence-like state, and growth arrest. SETDB1 silencing is accompanied by decreased expression of genes related to replication and the cell cycle. Analyses reveal CHK2 activation, the appearance of γH2AX and 53BP1 foci indicative of DNA damage, senescence-associated β-galactosidase–positive staining, and induction of p21.
The researchers further established that deficiency in CDC6, an essential regulator of DNA replication, reproduces the phenotype observed after SETDB1 inhibition: growth arrest, DNA damage, and senescence features. Treatment of several metastatic uveal melanoma cell lines (OMM1.3, OMM2.5, and OMM1) with mithramycin A, used as an anti-SETDB1 strategy, reduces their proliferation and induces apoptosis, as evidenced by PARP cleavage and quantification by annexin V staining. In a preclinical subcutaneous xenograft model in immunodeficient NSG mice, intraperitoneal administration of mithramycin A significantly impairs tumor growth, with good tolerability.
This work thus provides evidence that SETDB1 plays a decisive role in the growth of metastatic uveal melanoma and identifies this methyltransferase as a novel and relevant therapeutic target for this disease.