• English
    • Deutsch
View Item 
  •   OPARU Home
  • Medizinische Fakultät
  • Publikationen
  • View Item
  •   OPARU Home
  • Medizinische Fakultät
  • Publikationen
  • View Item
  • English 
    • English
    • Deutsch
  • Login
JavaScript is disabled for your browser. Some features of this site may not work without it.

A model of reversible dasatinib resistance in c-KIT-mutated acute myeloid leukemia with t(8;21)

Thumbnail
Download
vts_9390_14129.pdf (5.207Mb)
83 S
 
Veröffentlichung
2015-01-23
DOI
10.18725/OPARU-3542
Dissertation


Authors
Herrmann, Markus
Faculties
Medizinische Fakultät
License
Standard
https://oparu.uni-ulm.de/xmlui/license_v3
Abstract
KIT inhibition with dasatinib represents a promising approach to targeted therapy in t(8;21) acute myeloid leukemia (AML) and clinical trials are currently evaluating its clinical relevance. However, data on continuous long-term dasatinib exposure of AML cells are limited and the potential effects on KIT inhibition and dasatinib sensitivity are unexplored. Treatment-related resistance ultimately limits clinical efficacy of tyrosine kinase inhibitors (TKI), which could similarly apply to dasatinib in t(8;21) AML. In this study, we used the dasatinib-sensitive KITmut t(8;21) AML cell line Kasumi-1 to model, in a confined and control- lable way, molecular effects upon continuous dasatinib treatment. Long-term dasatinib exposure at clinically relevant levels resulted in markedly decreased drug-sensitivity of KITmut t(8;21) AML cells. Notably, all dasatinib-resistant clones lacked secondary KIT-mutations. Instead, persistent growth correlated with alterations in KIT expression levelsdthat is, either KIT overexpression with maintained downstream signaling or KIT downregulation with concomitant activation of alternate pathways. Although KIT overexpression was associated with retained receptor activity and STAT3 activation, KIT downregulation correlated with decreased STAT3 levels and increased ERK-signaling. Importantly, brief discontinuation of dasatinib restored dasatinib-sensitivity associated with reversal of signaling signatures similar to treatment-naive, dasatinib-sensitive cells. The observed desensitization of KITmut t(8;21) AML cells upon continuous dasatinib exposure suggests that therapy-related acquisition of resistance could pose significant limitations on therapeutic efficiency. Notably, we identified TKI-resistant states of transient nature that correlate with alterations in KIT expression and can be reversed upon brief inhibitor withdrawal. These findings indicate that discontinu- ing treatment maintains dasatinib sensitivity in KITmut AML cells.
Date created
2012
Subject Headings
Akute myeloische Leukämie [GND]
Rezeptor-Tyrosinkinasen [GND]
Dasatinib [MeSH]
Leukemia, myeloid, acute [MeSH]
Keywords
Kasumi-1; KIT; Resistenz; Tyrosine kinase inhibitor
Dewey Decimal Group
DDC 610 / Medicine & health

Metadata
Show full item record

Citation example

Herrmann, Markus (2015): A model of reversible dasatinib resistance in c-KIT-mutated acute myeloid leukemia with t(8;21). Open Access Repositorium der Universität Ulm. Dissertation. http://dx.doi.org/10.18725/OPARU-3542

Other citation formats



About OPARU | Contact Us
Impressum | Privacy statement
 

 

Advanced Search

Browse

All of OPARUCommunities & CollectionsFacultiesInstitutionsPersonsResource typesUlm SerialsDewey Decimal ClassesFundingThis CollectionFacultiesInstitutionsPersonsResource typesUlm SerialsDewey Decimal ClassesFunding

My Account

LoginRegister

Statistics

View Usage Statistics

About OPARU | Contact Us
Impressum | Privacy statement