Mechanism of Resistance to the WDR5 Inhibitor in MLL-Rearranged Leukemia

Drug resistance is a major problem often limiting the long-term effectiveness of targeted cancer therapeutics. Resistance can be acquired through mutations or amplification of the primary drug targets or activation of bypass signaling pathways. Considering the multifaceted function of WDR5 in human malignancies, WDR5 has emerged as an attractive drug target for the discovery of small-molecule inhibitors. In this study, we investigated if cancer cells might develop resistance to a highly potent WDR5 inhibitor. We established a drug-adapted cancer cell line and discovered that WDR5(P173L) mutation occurs in the resistant cells, which confers resistance by preventing target engagement of the inhibitor. This work elucidated the WDR5 inhibitor's potential resistance mechanism in a preclinical study as a reference for future study in the clinical stage.

Automated summary

Drug resistance is a major problem in targeted cancer therapy that can be caused by mutations or activation of bypass signaling pathways. WDR5 has been identified as a potential drug target due to its multifaceted function in cancer. This study found that cancer cells can develop resistance to a powerful WDR5 inhibitor through a specific mutation, providing insights into the resistance mechanism for future clinical research.