Pharmacological treats for SUMO addicts.

Non-oncogene addiction exploits cancer vulnerabilities resulting from altered cellular signaling pathways in response to oncogenic mutations that are not directly druggable. In this perspective, we address recent findings showing how the SUMOylation cascade provides a synthetic lethal target in the context of different malignant transformations. Functional genomics screens have revealed that the activation of oncogenes such as NOTCH1, MYC or KRAS generates a cancer-specific dependency on SUMOylation. Pharmacological targeting of the SUMOylation cascade induces cancer cell death in these settings, suggesting potential therapeutic applications in oncology. However, the physicochemical properties of the few currently available SUMOylation inhibitors preclude clear-cut investigations and clinical testing. We therefore encourage the development of better chemical probes targeting this multifaceted post-translational modification. Such optimized molecules would enable proof of concept studies to evaluate the therapeutic potential of non-oncogene addiction to SUMO.