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Velcrin compounds kill cancer cells expressing elevated levels of two cellular proteins, the PDE3A phosphodiesterase and the SLFN12 tRNase, by inducing PDE3A-SLFN12 complex formation. This results in activation of SLFN12, leading to digestion of its specific substrate, tRNA-Leu-TAA, inhibition of protein synthesis, and cell death, a process now called "tomoptosis". We hypothesized that velcrins such as BAY 2666605, a clinical velcrin, could be active against biomarker-positive uveal melanomas. We identified uveal melanoma cell lines expressing elevated levels of the biomarkers, PDE3A and SLFN12, and tested response to velcrin compounds in vitro and in vivo. We show that response correlates mechanistically with decreased levels of tRNA-Leu-TAA and inhibition of nascent protein synthesis and furthermore identify a potential mechanism of resistance.