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Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML.
Bourgeois, Wallace; Cutler, Jevon A; Aubrey, Brandon J; Wenge, Daniela V; Perner, Florian; Martucci, Cynthia; Henrich, Jill A; Klega, Kelly; Nowak, Radoslaw P; Donovan, Katherine A; Boileau, Meaghan; Wen, Yanhe; Hatton, Charlie; Apazidis, Athina A; Olsen, Sarah Naomi; Kirmani, Nadia; Pikman, Yana; Pollard, Jessica A; Perry, Jennifer A; Sperling, Adam S; Ebert, Benjamin L; McGeehan, Gerard M; Crompton, Brian D; Fischer, Eric S; Armstrong, Scott A.
Afiliación
  • Bourgeois W; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Cutler JA; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Aubrey BJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Wenge DV; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Perner F; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Martucci C; Internal Medicine C, University Medicine Greifswald, Greifswald, Germany.
  • Henrich JA; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Klega K; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Nowak RP; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Donovan KA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Boileau M; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • Wen Y; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Hatton C; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • Apazidis AA; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Olsen SN; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Kirmani N; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Pikman Y; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Pollard JA; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Perry JA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • Sperling AS; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Ebert BL; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • McGeehan GM; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • Crompton BD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • Fischer ES; Division of Hematology, Brigham and Women's Hospital, Boston, MA.
  • Armstrong SA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Blood ; 143(15): 1513-1527, 2024 Apr 11.
Article en En | MEDLINE | ID: mdl-38096371
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ftalimidas / Piperidonas / Leucemia Mieloide Aguda / Morfolinas / Proteína de la Leucemia Mieloide-Linfoide Límite: Humans Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ftalimidas / Piperidonas / Leucemia Mieloide Aguda / Morfolinas / Proteína de la Leucemia Mieloide-Linfoide Límite: Humans Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos