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Ref Type Journal Article
PMID (34555701)
Authors Darici S, Zavatti M, Braglia L, Accordi B, Serafin V, Horne GA, Manzoli L, Palumbo C, Huang X, Jørgensen HG, Marmiroli S
Title Synergistic cytotoxicity of dual PI3K/mTOR and FLT3 inhibition in FLT3-ITD AML cells.
Journal Vol Issue Date Pages Journal Short Title
Advances in biological regulation 82 2021 12 100830 Adv Biol Regul
URL
Abstract Text Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy, characterized by a heterogeneous genetic landscape and complex clonal evolution, with poor outcomes. Mutation at the internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic alterations in AML, associated with high relapse rates and poor survival due to the constitutive activation of the FLT3 receptor tyrosine kinase and its downstream effectors, such as PI3K signaling. Thus, aberrantly activated FLT3-kinase is regarded as an attractive target for therapy for this AML subtype, and a number of small molecule inhibitors of this kinase have been identified, some of which are approved for clinical practice. Nevertheless, acquired resistance to these molecules is often observed, leading to severe clinical outcomes. Therapeutic strategies to tackle resistance include combining FLT3 inhibitors with other antileukemic agents. Here, we report on the preclinical activity of the combination of the FLT3 inhibitor quizartinib with the dual PI3K/mTOR inhibitor PF-04691502 in FLT3-ITD cells. Briefly, we show that the association of these two molecules displays synergistic cytotoxicity in vitro in FLT3-ITD AML cells, triggering 90% cell death at nanomolar concentrations after 48 h.

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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
FLT3 exon 14 ins acute myeloid leukemia sensitive PF-04691502 + Quizartinib Preclinical - Cell culture Actionable In a preclinical study, the combination of PF-04691502 and Vanflyta (quizartinib) induced apoptosis and cell-cycle arrest and synergistically inhibited viability of an acute myeloid leukemia cell line harboring a FLT3-ITD mutation in culture (PMID: 34555701). 34555701