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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Heterogeneity of kinase inhibitor resistance mechanisms in GIST

B Liegl1, I Kepten, C Le

  • 1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. bernadette.liegl-atzwanger@med.uni-gaz.at

The Journal of Pathology
|July 16, 2008
PubMed

Insights

Most gastrointestinal stromal tumor (GIST) patients develop resistance to tyrosine kinase inhibitors (TKIs). This study reveals significant molecular heterogeneity in drug resistance mechanisms, with multiple secondary KIT mutations often found within individual patients, complicating treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Gastrointestinal stromal tumors (GISTs) frequently develop clinical resistance to tyrosine kinase inhibitors (TKIs) like imatinib and sunitinib.
  • The molecular basis for this TKI resistance, particularly the extent of heterogeneity within and between tumors, remains incompletely understood.

Purpose of the Study:

  • To investigate the inter- and intra-lesional heterogeneity of molecular drug-resistance mechanisms in GIST patients progressing on TKIs.
  • To characterize genomic alterations in KIT and PDGFRA genes across diverse GIST subtypes.

Main Methods:

  • Analysis of 53 GIST metastases from 14 patients who progressed on TKIs.
  • Systematic genomic characterization using D-HPLC and mutation-specific PCR for KIT and PDGFRA mutations.
  • Fluorescence in situ hybridization (FISH) to detect KIT gene amplification.

Main Results:

  • Primary oncogenic KIT mutations were identified in 79% of patients.
  • 83% of patients with primary KIT mutations acquired secondary KIT resistance mutations, often multiple, in separate or the same metastases.
  • Secondary mutations targeted the KIT ATP binding pocket and kinase catalytic regions; KIT amplification was observed in a subset of cases.

Conclusions:

  • Extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification exists in progressing GIST.
  • Resistance mechanisms differ fundamentally in KIT/PDGFRA wild-type GISTs or those with unusual morphology/loss of KIT expression.
  • This heterogeneity presents significant therapeutic challenges for salvaging patients after TKI monotherapy failure.

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