Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia

ABSTRACT: Small molecules that target the MENIN-KMT2A protein-protein interaction (Menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A, 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 and has 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. We show that the superior activity of Mezigdomide compared to Lenalidomide or Iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent Mezigdomide was efficacious in five patient derived xenograft (PDX) models of KMT2A-r and one NPM1c AML. The combination of Mezigdomide with a Menin inhibitor increased survival and prevented the development of recently described MEN1 mutations. 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.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD041735 | Pride | 2024-02-15

REPOSITORIES: Pride