Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants Academic Article uri icon

Overview

MeSH Major

  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl

abstract

  • The success of targeting kinases in cancer with small molecule inhibitors has been tempered by the emergence of drug-resistant kinase domain mutations. In patients with chronic myeloid leukemia treated with ABL inhibitors, BCR-ABL kinase domain mutations are the principal mechanism of relapse. Certain mutations are occasionally detected before treatment, suggesting increased fitness relative to wild-type p210 BCR-ABL. We evaluated the oncogenicity of eight kinase inhibitor-resistant BCR-ABL mutants and found a spectrum of potencies greater or less than p210. Although most fitness alterations correlate with changes in kinase activity, this is not the case with the T315I BCR-ABL mutation that confers clinical resistance to all currently approved ABL kinase inhibitors. Through global phosphoproteome analysis, we identified a unique phosphosubstrate signature associated with each drug-resistant allele, including a shift in phosphorylation of two tyrosines (Tyr253 and Tyr257) in the ATP binding loop (P-loop) of BCR-ABL when Thr315 is Ile or Ala. Mutational analysis of these tyrosines in the context of Thr315 mutations demonstrates that the identity of the gatekeeper residue impacts oncogenicity by altered P-loop phosphorylation. Therefore, mutations that confer clinical resistance to kinase inhibitors can substantially alter kinase function and confer novel biological properties that may impact disease progression.

publication date

  • December 19, 2006

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1698443

Digital Object Identifier (DOI)

  • 10.1073/pnas.0609239103

PubMed ID

  • 17164333

Additional Document Info

start page

  • 19466

end page

  • 71

volume

  • 103

number

  • 51