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Ref Type Journal Article
PMID (26634271)
Authors Garcia JS, Huang M, Medeiros BC, Mitchell BS
Title Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 8
Date 2016 Apr 15
URL
Abstract Text This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action.The cytotoxic effects of ixazomib treatment were analyzed in human acute myelogenous leukemia (AML) cell lines and primary AML samples expressing wild-type or mutated NPM1 (NPMc(+)). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and Western blots.Apoptosis induced by ixazomib was abrogated by knockdown of NPM1/NPMc(+)expression using an inducible shRNA construct and enhanced by NPMc(+)overexpression. Cytotoxicity was associated with superoxide generation and was reduced by the addition of the antioxidant N-acetylcysteine. AML cells expressing NPMc(+)had significantly reduced levels of intracellular glutathione and NADPH associated with reduced antioxidant responses to drug treatment. Treatment of 3 patients with relapsed NPMc(+)AML resulted in an antileukemic effect in 1 patient as demonstrated by a marked reduction of leukemic blasts in the peripheral blood. Efficacy was associated with superoxide generation, reduced glutathione levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells.In this study, a direct association was observed between NPMc(+)expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib.

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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
NPM1 exon12 acute myeloid leukemia sensitive Ixazomib + Vorinostat Preclinical - Cell culture Actionable In a preclinical study, Ixazomib (MLN9708) and Zolinza (vorinostat) synergistically induced apoptosis in NPMc+ (due to NPM1 exon 12 mutations) acute myeloid leukemia cells in culture (PMID: 26634271). 26634271
NPM1 exon12 acute myeloid leukemia predicted - sensitive Ixazomib Case Reports/Case Series Actionable In a clinical study, Ixazomib (MLN9708) treatment resulted in significantly reduced peripheral blast cells in a NPMc+ (due to NPM1 exon 12 mutations) acute myeloid leukemia (AML) patient, and demonstrated selective toxicity towards NPMc+ AML cell lines in culture (PMID: 26634271). 26634271