Pharmacological impact of FLT3 mutations on receptor activity and responsiveness to tyrosine kinase inhibitors

Marensi, Vanessa; Keeshan, Karen; MacEwan, David J.

doi:10.1016/j.bcp.2020.114348

Cited by 12 publications

(10 citation statements)

References 158 publications

(184 reference statements)

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“…5A). This finding and the suppressed phosphorylation of FLT3-ITD validate the anticipated effects of AC220 (Majothi et al 2020;Marensi et al 2021;Scholl et al 2020). RGFP966 reduced the levels of FLT3-ITD, and this was associated with a reduction of pY591-FLT3-ITD.…”

Section: Ac220 and Rgfp966 Promote Their Target Engagement And Attenuate Dna Repair Proteinssupporting

confidence: 72%

“…The membrane-bound FMS-like tyrosine kinase-3 (FLT3) is activated by the FLT3 ligand and contributes to the development of hematopoietic cells. FLT3 is encoded on chromosome 13q12.2 and consists of five extracellular, immunoglobulin-like domains, a transmembrane domain, a juxtamembrane domain, and an intracellular tyrosine kinase domain (Majothi et al 2020 ; Marensi et al 2021 ; Scholl et al 2020 ). Mutations in FLT3 promote cell growth and chemoresistance and lead to AML with poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

et al. 2021

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Acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase (FLT3) is a clinically unresolved problem. AML cells frequently have a dysregulated expression and activity of epigenetic modulators of the histone deacetylase (HDAC) family. Therefore, we tested whether a combined inhibition of mutant FLT3 and class I HDACs is effective against AML cells. Low nanomolar doses of the FLT3 inhibitor (FLT3i) AC220 and an inhibition of class I HDACs with nanomolar concentrations of FK228 or micromolar doses of the HDAC3 specific agent RGFP966 synergistically induce apoptosis of AML cells that carry hyperactive FLT3 with an internal tandem duplication (FLT3-ITD). This does not occur in leukemic cells with wild-type FLT3 and without FLT3, suggesting a preferential toxicity of this combination against cells with mutant FLT3. Moreover, nanomolar doses of the new FLT3i marbotinib combine favorably with FK228 against leukemic cells with FLT3-ITD. The combinatorial treatments potentiated their suppressive effects on the tyrosine phosphorylation and stability of FLT3-ITD and its downstream signaling to the kinases ERK1/ERK2 and the inducible transcription factor STAT5. The beneficial pro-apoptotic effects of FLT3i and HDACi against leukemic cells with mutant FLT3 are associated with dose- and drug-dependent alterations of cell cycle distribution and DNA damage. This is linked to a modulation of the tumor-suppressive transcription factor p53 and its target cyclin-dependent kinase inhibitor p21. While HDACi induce p21, AC220 suppresses the expression of p53 and p21. Furthermore, we show that both FLT3-ITD and class I HDAC activity promote the expression of the checkpoint kinases CHK1 and WEE1, thymidylate synthase, and the DNA repair protein RAD51 in leukemic cells. A genetic depletion of HDAC3 attenuates the expression of such proteins. Thus, class I HDACs and hyperactive FLT3 appear to be valid targets in AML cells with mutant FLT3.

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Section: Ac220 and Rgfp966 Promote Their Target Engagement And Attenuate Dna Repair Proteinssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

et al. 2021

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“…As we noted a loss of RAF1 in NB4 cells that were treated with hydroxyurea but not in hydroxyurea-treated K562 cells, we hypothesized that RAF1 protected K562 cells from cytotoxic effects of hydroxyurea. Accordingly, we focused on CML cells and then turned to AML cells with FLT3-ITD, which are clinically challenging [16,17,47]. In contrast to this, APL is mostly curable [51].…”

Section: Discussionmentioning

confidence: 99%

“…We chose AML cells with mutant FLT3 because, like BCR-ABL1, it induces RAF, BCL-XL, and other pro-survival proteins [27,45,46]. Moreover, FLT3-ITD is an unfavorable prognostic marker that is associated with chemotherapy resistance and relapse [16,17,47].…”

Section: Raf Is a Target In Hydroxyurea-treated Flt3-itd-positive Aml Cellsmentioning

confidence: 99%

“…FLT3-TKD mutants drastically decrease the sensitivity of FLT3 to TKi [16,17,47]. Due to this unresolved clinical issue, we tested navitoclax and hydroxyurea on Ba/F3 leukemia cells with FLT3-ITD (FLT3 with internal tandem duplication at 598) and therapyassociated FLT3-ITD/TKD mutants (FLT3-ITD+D835Y and FLT3-ITD+N676K).…”

Section: Navitoclax Combines Favorably With Hydroxyurea Against Flt3 Mutant Aml Cellsmentioning

confidence: 99%

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Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

Pons

Zeyn

Zahn

et al. 2021

Cancers

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The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations.

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Pharmacodynamic Polymorphisms

Martínez

Cerpa

Varela

et al. 2022

The ADME Encyclopedia

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Pharmacological impact of FLT3 mutations on receptor activity and responsiveness to tyrosine kinase inhibitors

Cited by 12 publications

References 158 publications

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

Pharmacodynamic Polymorphisms

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