Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia.

Leukemia
Fei FeiNora Heisterkamp

Abstract

Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Philadelphia chromosome-positive (Ph-positive) leukemias. At a once-daily dose and a relatively short half-life of 3-5 h, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell-surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low-dose dasatinib monotherapy will be effecti...Continue Reading

References

Oct 23, 1997·The Journal of Experimental Medicine·D ScholsE De Clercq
Jun 20, 1998·The Journal of Biological Chemistry·N I TarasovaC J Michejda
Jun 13, 2000·The Journal of Biological Chemistry·J M LionbergerT E Smithgall
Aug 28, 2002·Reviews in Clinical and Experimental Hematology·Stefan FaderlHagop M Kantarjian
Nov 2, 2002·The EMBO Journal·Agata KlejmanTomasz Skorski
Feb 20, 2003·The Journal of Experimental Medicine·Aleksandra M GlodekLeslie E Silberstein
Jul 17, 2004·Science·Neil P ShahCharles L Sawyers
May 19, 2006·Cancer Research·Suparna MishraJohn Groffen
Jun 16, 2006·The New England Journal of Medicine·Moshe TalpazCharles L Sawyers
Nov 2, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yiguo HuShaoguang Li
Oct 26, 2007·Molecular Cancer·Pavinder KaurNora Heisterkamp
Dec 7, 2007·Immunology Letters·Laura Patrussi, Cosima T Baldari
Jan 15, 2008·Leukemia Research·Yasuyuki DeguchiTaira Maekawa
Jan 25, 2008·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Susan J Keam
Jan 29, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michael BraveRichard Pazdur
Apr 19, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Lisa J ChristopherRamaswamy A Iyer
May 1, 2008·Molecular Cancer Therapeutics·Ellen WeisbergJames D Griffin
Jun 11, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Neil P ShahAndreas Hochhaus
Oct 3, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Seiichi OkabeKazuma Ohyashiki
Dec 17, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sara RedaelliFrank Boschelli
Dec 18, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Donald Wong, Walter Korz

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Citations

Jul 25, 2012·Nature Reviews. Cancer·Thomas O'HareMichael W Deininger
Mar 13, 2013·The Journal of Experimental Medicine·Reshmi ParameswaranJohn Groffen
Apr 15, 2010·Molecular Cancer Therapeutics·Fei FeiNora Heisterkamp
Jun 6, 2014·Leukemia & Lymphoma·Matthew KuHarshal Nandurkar
Mar 27, 2015·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Yi-Sen ChengXue-Song Yang
Aug 31, 2012·Oncoimmunology·Niklas FeldhahnNora Heisterkamp
Jan 22, 2013·Leukemia Research·Rocky PramanikSteven D Mittelman
Sep 7, 2016·Expert Opinion on Drug Discovery·Federica BarbieriTullio Florio
Mar 28, 2018·Journal of Experimental & Clinical Cancer Research : CR·Helicia PazNora Heisterkamp
Feb 22, 2012·Clinical Medicine Insights. Oncology·Lydia Lee, Adele K Fielding
Apr 14, 2019·Journal of Cellular Physiology·Jessica L HeathGary S Stein
Apr 24, 2019·The Journal of Pharmacology and Experimental Therapeutics·Werner J GeldenhuysLaura F Gibson
Jun 15, 2011·Expert Review of Hematology·Edward Allan R Sison, Patrick Brown
Jan 1, 2015·Expert Opinion on Orphan Drugs·Cristina Varallo-RodriguezMeir Wetzler
Nov 26, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Thomas O'HareBrian J Druker
Jun 12, 2013·Molecular Cancer Research : MCR·Edward Allan R SisonPatrick Brown
May 7, 2021·Nature Reviews. Cancer·Andrew E WhiteleyDorothy A Sipkins
Jul 3, 2021·International Journal of Molecular Sciences·Agnieszka KaczmarskaMonika Lejman
Jul 29, 2021·Journal of Cellular and Molecular Medicine·Nam-Sook ParkByeong-Churl Jang

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Methods Mentioned

BETA
flow cytometry
electrophoresis

Software Mentioned

SPSS

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