Reference Detail

Ref Type

Journal Article

PMID

(35017466)

Authors

Fiskus W, Boettcher S, Daver N, Mill CP, Sasaki K, Birdwell CE, Davis JA, Takahashi K, Kadia TM, DiNardo CD, Jin Q, Qi Y, Su X, McGeehan GM, Khoury JD, Ebert BL, Bhalla KN

Title

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer journal	12	1	2022 01 11	5	Blood Cancer J

URL

Abstract Text

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KMT2A rearrange FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Revumenib + Venetoclax	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Revumenib and Venclexta (venetoclax) reduced the leukemia burden and improved survival in an acute myeloid leukemia cell line xenograft model harboring a KMT2A rearrangement and FLT3-ITD compared to either treatment alone, and demonstrated synergy in culture, resulting in decreased viability (PMID: 35017466).	35017466
KMT2A rearrange FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Revumenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Revumenib reduced the leukemia burden and improved survival in an acute myeloid leukemia cell line xenograft model harboring a KMT2A rearrangement (MLL-r) and FLT3-ITD compared to vehicle-treated, but only inhibited cell viability after prolonged treatment in culture (PMID: 35017466).	35017466