scholarly journals Human liver stem cell-derived extracellular vesicles enhance cancer stem cell sensitivity to tyrosine kinase inhibitors through Akt/mTOR/PTEN combined modulation

Oncotarget ◽  
2018 ◽  
Vol 9 (90) ◽  
pp. 36151-36165 ◽  
Author(s):  
Valentina Fonsato ◽  
Michela De Lena ◽  
Stefania Tritta ◽  
Alessia Brossa ◽  
Ruggero Calvetti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Extracellular Vesicles ◽  
Human Liver ◽  
Kinase Inhibitors ◽  
Cell Sensitivity

Abstract 234: Physiological Toxicity Assessment of Tyrosine Kinase Inhibitors with Human Induced Pluripotent Stem Cell Cardiomyocytes

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jayna Stohlman ◽  
Derek Schocken ◽  
Jose Vicente ◽  
Dulciana Chan ◽  
Lars Johannesen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Pluripotent Stem Cell ◽  
Kinase Inhibitors ◽  
Induced Pluripotent Stem Cell ◽  
Assay Sensitivity ◽  
Cancer Management ◽  
Induced Pluripotent ◽  
Acute And Chronic Exposure

Tyrosine kinase inhibitors (TKIs) have improved targeted therapeutics for cancer management despite possible cardiac side effects, including decreased contractility. A combination microelectrode and impedance platform was used to assess field potential (FP) electrical activity and contractility, respectively, after acute and chronic exposure of six TKIs on human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). Four non-TKI drugs were tested to confirm assay sensitivity. hERG current inhibitors dofetilide and pentamidine increased beat rate (BR) corrected FP duration (FPDc). Dofetilide (6μM) induced transient early afterdepolarizations (EADs), characterized as ectopic beats/notching in the FP signal, and decreased impedance amplitude (BAmp) at 48hrs. Multi-channel blocker amiodarone (2μM) acutely decreased FPDc, with quiescence up to 1hr, and increased BAmp after 24hrs. Doxorubicin decreased BAmp, inducing quiescence starting at 48hrs (5μM and 10μM). Nilotinib, sorafenib and sunitinib, which have varying documented risks of clinical QT prolongation and/or cardiotoxicity, increased FPDc. With highest tested doses, nilotinib (6μM) generated persistent EADs and increased BR, sunitinib (2.5μM) produced tachyarrhythmias with minimal impedance-evident contractions that recovered by 24hrs, and sorafenib (10μM) induced quiescence that recovered by 3hrs. Imatinib, erlotinib and lapatinib, which have fewer clinical cardtiotoxic effects, did not cause rhythm disturbances. Erlotinib and lapatinib had no significant effect on FPDc, lapatinib (2.5μM and 5μM) decreased BR, while imatinib (15μM) acutely increased FPDc and increased BR after 48hrs. Tandem electrical and impedance screening in hiPSC-CMs for drug cardiotoxicity was consistent with the clinical experience for TKIs, suggesting its potential utility for preclinical cardiotoxicity assessment for proarrhythmia and decreased contractility.

Three decades of transplantation for chronic myeloid leukemia: what have we learned?

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 755-763 ◽  
Author(s):  
Jiří Pavlů ◽  
Richard M. Szydlo ◽  
John M. Goldman ◽  
Jane F. Apperley
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Hematopoietic Stem

Abstract Last year marked 30 years of hematopoietic stem cell transplantation as a curative treatment of chronic myeloid leukemia (CML). Initially studies used stem cells from identical twins but techniques rapidly developed to use cells first from HLA-identical siblings and later unrelated donors. During the 1990s CML became the most frequent indication for allogeneic transplantation worldwide. This, together with the relative biologic homogeneity of CML in chronic phase, its responsiveness to graft-versus-leukemia effect and the ability to monitor low level residual disease placed CML at the forefront of research into different strategies of stem cell transplantation. The introduction of BCR-ABL1 tyrosine kinase inhibitors during the last decade resulted in long-term disease control in the majority of patients with CML. In those who fail to respond and/or develop intolerance to these agents, transplantation remains an effective therapeutic solution. The combination of tyrosine kinase inhibitors with transplantation is an exciting new strategy and it provides inspiration for similar approaches in other malignancies.

The Nonspecific Binding of Tyrosine Kinase Inhibitors to Human Liver Microsomes

2015 ◽  
Vol 43 (12) ◽  
pp. 1934-1937 ◽  
Author(s):  
Kushari Burns ◽  
Pramod C. Nair ◽  
Andrew Rowland ◽  
Peter I. Mackenzie ◽  
Kathleen M. Knights ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Human Liver ◽  
Kinase Inhibitors ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Nonspecific Binding

scholarly journals FLT3 Mutations in Early T-Cell Precursor ALL Characterize a Stem Cell Like Leukemia and Imply the Clinical Use of Tyrosine Kinase Inhibitors

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53190 ◽  
Author(s):  
Martin Neumann ◽  
Ebru Coskun ◽  
Lars Fransecky ◽  
Liliana H. Mochmann ◽  
Isabelle Bartram ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Clinical Use ◽  
Cell Precursor ◽  
Flt3 Mutations

scholarly journals DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

2020 ◽  
Vol 52 (10) ◽  
pp. 1663-1672
Author(s):  
Chun Shik Park ◽  
H. Daniel Lacorazza
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Stem Cell Population ◽  
Leukemia Stem Cells ◽  
Treatment Free Remission

Abstract Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient’s immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission.

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