PF554 A GENOME-WIDE CRISPR SCREEN IDENTIFIES TOP2B AS AN ACQUIRED DRUGGABLE VULNERABILITY IN THE CONTEXT OF IMID RESISTANCE

Abstract

Immunomodulatory thalidomide analogues (IMiDs, lenalidomide [LEN] and pomalidomide [POM]) modify the substrate specificity of the CUL4A‐DDB1‐RBX1 E3 ubiquitin ligase complex through a direct interaction with cereblon (CRBN). In the presence of IMiDs, CUL4ACRBN induces proteasomal degradation of IKZF1 and IKZF3, which are key oncogenic transcription factors in multiple myeloma (MM). Unfortunately, continued IMiD exposure leads to acquired drug resistance in the majority of patients and IMiD‐refractoriness conveys poor prognosis. Whereas perturbations of CRBN and directly linked elements of the CUL4A complex are known to mediate IMiD resistance, mechanistic insight downstream of the CUL4ACRBN ..