دورية أكاديمية
Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML.
| العنوان: | Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML. |
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| المؤلفون: | 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.; Internal Medicine C, University Medicine Greifswald, Greifswald, Germany., Martucci C; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA., 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; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA., Donovan KA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA., Boileau M; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Wen Y; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Hatton C; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and 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; Department of Cancer Biology, Dana-Farber Cancer Institute, 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; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Sperling AS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Division of Hematology, Brigham and Women's Hospital, Boston, MA., Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Howard Hughes Medical Institute, Boston, MA., McGeehan GM; Syndax Pharmaceuticals, Waltham, MA., Crompton BD; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Fischer ES; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA., Armstrong SA; Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA. |
| المصدر: | Blood [Blood] 2024 Apr 11; Vol. 143 (15), pp. 1513-1527. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Myeloid-Lymphoid Leukemia Protein*/genetics , Myeloid-Lymphoid Leukemia Protein*/metabolism , Leukemia, Myeloid, Acute*/drug therapy , Leukemia, Myeloid, Acute*/genetics , Leukemia, Myeloid, Acute*/metabolism , Morpholines* , Phthalimides* , Piperidones*, Humans ; Lenalidomide/therapeutic use ; Transcription Factors/genetics ; Mutation |
| مستخلص: | 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. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.) |
| التعليقات: | Comment in: Blood. 2024 Apr 11;143(15):1438-1439. (PMID: 38602697) |
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| معلومات مُعتمدة: | P50 CA206963 United States CA NCI NIH HHS; F32 CA250240 United States CA NCI NIH HHS; R01 CA176745 United States CA NCI NIH HHS; K99 CA279888 United States CA NCI NIH HHS; T32 HL007574 United States HL NHLBI NIH HHS; K08 CA252174 United States CA NCI NIH HHS; R01 CA204639 United States CA NCI NIH HHS; P01 CA066996 United States CA NCI NIH HHS |
| المشرفين على المادة: | F0P408N6V4 (Lenalidomide) 8V66F27X44 (iberdomide) 149025-06-9 (Myeloid-Lymphoid Leukemia Protein) 0 (Transcription Factors) 0 (Morpholines) 0 (Phthalimides) 0 (Piperidones) |
| تواريخ الأحداث: | Date Created: 20231214 Date Completed: 20240412 Latest Revision: 20240426 |
| رمز التحديث: | 20240426 |
| مُعرف محوري في PubMed: | PMC11033588 |
| DOI: | 10.1182/blood.2023021105 |
| PMID: | 38096371 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2023021105 |