Fms-like tyrosine kinase 3 is a regulator of the cardiac side population in mice

Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells and a target of tyrosine kinase inhibitors. Flt3-targeting tyrosine kinase inhibitors can have cardiovascular side effects. Flt3 and its ligand (Flt3L) are expressed in the heart, but little is known about their physiological functions. Here, we show that cardiac side population progenitor cells (SP-CPCs) from mice produce and are responsive to Flt3L. Compared with wild-type, flt3L−/− mice have less SP-CPCs with less contribution of CD45−CD34+ cells and lower expression of genes related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing, flt3L−/− SP-CPCs show increased proliferation and less vasculogenic commitment, whereas Akt phosphorylation is lower. Notably, proliferation and differentiation can be partially restored towards wild-type levels in the presence of alternative receptor tyrosine kinase-activating growth factors signaling through Akt. The lower vasculogenic potential of flt3L−/− SP-CPCs reflects in decreased microvascularisation and lower systolic function of flt3L−/− hearts. Thus, Flt3 regulates phenotype and function of murine SP-CPCs and contributes to cellular and molecular properties that are relevant for their cardiovasculogenic potential.

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Design of Chimeric Histone Deacetylase- and Tyrosine Kinase-Inhibitors: A Series of Imatinib Hybrides as Potent Inhibitors of Wild-Type and Mutant BCR-ABL, PDGF-Rβ, and Histone Deacetylases†

Journal of Medicinal Chemistry ◽

10.1021/jm800988r ◽

2009 ◽

Vol 52 (8) ◽

pp. 2265-2279 ◽

Cited By ~ 57

Author(s):

Siavosh Mahboobi ◽

Stefan Dove ◽

Andreas Sellmer ◽

Matthias Winkler ◽

Emerich Eichhorn ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Histone Deacetylase ◽

Histone Deacetylases ◽

Kinase Inhibitors ◽

Wild Type

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MERTK Promotes Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors in Non–small Cell Lung Cancers Expressing Wild-type EGFR Family Members

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-0040 ◽

2018 ◽

Vol 24 (24) ◽

pp. 6523-6535 ◽

Cited By ~ 8

Author(s):

Dan Yan ◽

Rebecca E. Parker ◽

Xiaodong Wang ◽

Stephen V. Frye ◽

H. Shelton Earp ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Small Cell ◽

Wild Type ◽

Small Cell Lung ◽

Lung Cancers ◽

Egfr Tyrosine Kinase ◽

Egfr Tyrosine Kinase Inhibitors ◽

Egfr Family

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The Use of EGFR Tyrosine Kinase Inhibitors in EGFR Wild-Type Non-Small-Cell Lung Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-016-0394-4 ◽

2016 ◽

Vol 17 (4) ◽

Cited By ~ 10

Author(s):

Thomas E. Stinchcombe

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitors ◽

Cell Lung Cancer ◽

Kinase Inhibitors ◽

Small Cell ◽

Wild Type ◽

Small Cell Lung ◽

Egfr Tyrosine Kinase Inhibitors

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FOXO transcription factor activity is partially retained in quiescent CML stem cells and induced by tyrosine kinase inhibitors in CML progenitor cells

Blood ◽

10.1182/blood-2009-06-226621 ◽

2009 ◽

Cited By ~ 5

Author(s):

F. Pellicano ◽

D. Cilloni ◽

G. V. Helgason ◽

F. Messa ◽

C. Panuzzo ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Tyrosine Kinase ◽

Progenitor Cells ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Transcription Factor Activity ◽

Factor Activity ◽

Foxo Transcription Factor

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Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms222111833 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11833

Author(s):

Cristina Minnelli ◽

Laura Cianfruglia ◽

Emiliano Laudadio ◽

Mobbili Giovanna ◽

Roberta Galeazzi ◽

...

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Small Cell ◽

Egfr Signaling ◽

Wild Type ◽

Small Cell Lung ◽

And Migration

The epidermal growth factor receptor (EGFR) is one of the most well-studied molecular targets in non-small cell lung cancer (NSCLC) and tyrosine kinase inhibitors have been shown to be effective in the treatment of advanced NSCLC. Nevertheless, the efficacy of tyrosine kinase inhibitors could be compromised by additional mutations in EGFR and compensatory activations of other pathways. Epigallocatechin-3-gallate (EGCG), the main bioactive molecule in green tea, acts as a tyrosine kinase inhibitor toward cancer cells overexpressing EGFR (wild-type). However, little information has been reported on the effect of EGCG on EGFR with activating mutations. In this study, we evaluated the ability of EGCG to inhibit EGFR signaling activation in three different NSCLC cell lines containing wild-type EGFR or EGFR with additional mutations. The effect on proliferation, apoptosis, migration, and vinculin expression was then studied. Overall, our results demonstrate that EGCG polyphenol inhibits cell proliferation and migration in NSCLC cell lines, although with different efficacy and mechanisms. These data may be of interest for an evaluation of the use of EGCG as an adjunct to NSCLC therapies.

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Moving Targets in Hepatocellular Carcinoma: Hepatic Progenitor Cells as Novel Targets for Tyrosine Kinase Inhibitors

Gastroenterology ◽

10.1053/j.gastro.2008.07.036 ◽

2008 ◽

Vol 135 (3) ◽

pp. 733-735 ◽

Cited By ~ 6

Author(s):

Abby Siegel

Keyword(s):

Hepatocellular Carcinoma ◽

Tyrosine Kinase ◽

Progenitor Cells ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Hepatic Progenitor Cells ◽

Moving Targets ◽

Novel Targets

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Is there a benefit on survival of tyrosine-kinase inhibitors versus chemotherapy in first line in mutated EGFR patients with advanced non-small cell cancer (NSCLC)? A meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18020 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18020-e18020

Author(s):

Gaetan Des Guetz ◽

Bernard Uzzan ◽

Kader Chouahnia ◽

Patrick Nicolas ◽

Jean F. Morere

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Cell Cancer ◽

Random Effect Model ◽

Lung Neoplasm ◽

Phase Iii ◽

Wild Type ◽

Effect Model

e18020 Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable. Therefore, we performed a publication-based meta-analysis to further assess this issue. Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, TKI, EGFR mutation, survival). We also searched for relevant abstracts in proceedings of ASCO, ESMO, WCLC annual meetings. We cross-checked all references from all articles. Only phase III randomized controlled trials comparing TKI and chemotherapy were included. We used EasyMA software. Results: The 6 eligible studies included 2223 patients (516 males, 1688 females, mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four studies assessed gefitinib, 2 erlotinib. Chemotherapies were doublets including a platinum salt. Four studies included only mutated patients. Compared to chemotherapy, EGFR TKIs significantly improved PFS (HR=0.39, 95 % CI 0.28-0.53, random effect model). Conversely, OS was similar among patients who first received TKI or chemotherapy (HR=1.00, CI 0.83-1.22, fixed effect model). PFS was significantly worse among non mutated patients in the 2 studies including both mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning side-effects, rash, diarrhoea and interstitial lung disease were significantly more frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/vomiting (0.19) and haematological disorders were all significantly more frequent after chemotherapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18 and 0.26). Conclusions: The major discrepancy between a markedly improved PFS and a similar OS after TKI compared with chemotherapy could be related to the high level of crossing-over between the 2 groups. We found no detrimental effect on OS of TKIs among wild-type patients.

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