AI Article Synopsis

  • Small molecules known as menin inhibitors, which target the menin-KMT2A protein interactions, are showing promise in clinical trials for certain types of acute myeloid leukemia (AML), but combination therapy is needed to enhance treatment and reduce resistance.
  • * Researchers have identified IKZF1/IKAROS as a significant target in KMT2A-rearranged AML and introduced a new IKAROS degrader called mezigdomide, which shows improved effectiveness compared to older treatments like lenalidomide and iberdomide.
  • * In preclinical studies, mezigdomide not only works well on its own but also significantly boosts the effectiveness of menin inhibitors, suggesting it could be a strong candidate for early phase

Article Abstract

Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)-rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show that mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to lenalidomide and iberdomide. Further, we demonstrate that mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with menin inhibitors, including in MEN1 mutant models. We show that the superior activity of mezigdomide compared with lenalidomide or iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent mezigdomide was efficacious in 5 patient-derived xenograft models of KMT2A-r and 1 NPM1c AML. The combination of mezigdomide with the menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single agent or in combination with menin inhibitors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11033588PMC
http://dx.doi.org/10.1182/blood.2023021105DOI Listing

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