Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations

Chuanjiang Yu; Rama Krishna Kancha; Justus Duyster

doi:10.1371/journal.pone.0097116

Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations

PLoS One. 2014 May 21;9(5):e97116. doi: 10.1371/journal.pone.0097116. eCollection 2014.

Authors

Chuanjiang Yu¹, Rama Krishna Kancha¹, Justus Duyster¹

Affiliation

¹ Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.

Abstract

FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Benzoquinones / pharmacology*
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Leukemic*
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / genetics
HSP90 Heat-Shock Proteins / metabolism
Humans
Lactams, Macrocyclic / pharmacology*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Mice
Molecular Sequence Data
Mutation
Protein Binding
Protein Kinase Inhibitors / pharmacology
Protein Stability / drug effects
Protein Structure, Tertiary
Proteolysis
Sequence Alignment
Signal Transduction
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / genetics*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Benzoquinones
HSP90 Heat-Shock Proteins
Lactams, Macrocyclic
Protein Kinase Inhibitors
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
tanespimycin
FLT3 protein, human
fms-Like Tyrosine Kinase 3
geldanamycin

Grants and funding

JD is supported by a grant from the José Carreras Leukämie-Stiftung. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.