Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3 -mutated acute myeloid leukemias: from concept to clinical trial

Haematologica
Weiguo ZhangMichael Andreeff

Abstract

Targeted therapies against FLT3-mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (e.g., XPO1) and FLT3 concomitantly may be therapeutically effective. Here we report on the combinatorial inhibition of XPO1 using selinexor and FLT3 using sorafenib. Selinexor exerted marked cell killing of human and murine FLT3-mutant acute myeloid leukemia cells, including those harboring internal tandem duplication and/or tyrosine kinase domain point mutations. Interestingly, selinexor treatment of murine FLT3-mutant acute myeloid leukemia cells activated FLT3 and its downstream MAPK or AKT signaling pathways. When combined with sorafenib, selinexor triggered marked synergistic pro-apoptotic effects. This was preceded by elevated nuclear levels of ERK, AKT, NFκB, and FOXO3a. Five days of in vitro combination treatment using low doses (i.e., 5 to 10 nM) of each agent promoted early myel...Continue Reading

Citations

Jun 25, 2019·Current Hematologic Malignancy Reports·Ipsita PalChangchun Deng
Jun 25, 2019·Expert Review of Hematology·Eran Tallis, Gautam Borthakur
Jun 4, 2020·Journal of Hematology & Oncology·Nancy G Azizian, Yulin Li
Jul 7, 2020·Leukemia·Boaz Nachmias, Aaron D Schimmer
Jun 17, 2020·Leukemia & Lymphoma·Janek S WalkerRosa Lapalombella
Nov 12, 2020·Nature Reviews. Clinical Oncology·Asfar S AzmiRamzi M Mohammad
Sep 26, 2020·Blood Reviews·Katerina BenkovaTomas Jelinek
Sep 2, 2021·Technology in Cancer Research & Treatment·Li-Jia PanYe-Ming Wu

❮ Previous
Next ❯

Methods Mentioned

BETA
fluorescence-activated cell sorting
electrophoresis
Infrared Imaging
light microscopy
flow cytometry
xenograft
xenografts

Clinical Trials Mentioned

NCT02091245
NCT02088541
NCT02249091
NCT02530476

Software Mentioned

Scion Imaging system
CalcuSyn

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

Autophagy & Aging: Inhibitors

The feed focuses on the role of nuclear export inhibitors and their effect on autophagy and the aging process.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.