Making the undruggable druggable: Rapid degradation of oncogenic transcription factors using the FKBP12-36 dTAG system

Oncogenes are well established to be overexpressed in cancer. One of the ways they are regulated are via proteins known as transcription factors (TFs) which aid in the up- or down-expression of target genes, and these TFs themselves are often oncogenic. Although some therapies such IMiDs, used in the treatment of multiple myeloma (MM), are able to target specific TFs for degradation, in general TFs are diNicult to target therapeutically and are generally considered “undruggable”. This is due to the challenge of disrupting protein-DNA or protein-protein interactions via small molecules, compounded by the fact they lack specific ligand binding pockets found in other “druggable” targets, e.g. enzymes and receptors. Additionally, the essential nature of oncogenes means they often cannot be genetically deleted while keeping cells viable, making it diNicult to study their function. The degron tag (dTAG) system bypasses this problem by allowing inducible protein degradation. In this system, the target gene is edited to add a degrader to the protein of interest (POI). Here, I talk through the process of editing cell lines via CRISPR/Cas9 gene editing to incorporate the FKBP12F36V degrader domain. Genetically engineering cells to be tagged for degradation allows rapid, inducible protein degradation, and limits the possibility for secondary or compensatory eNects in the cell. This has allowed me to generate a model system to look at the immediate consequences of specific TF degradation in MM and understand their functional and transcriptional roles.

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