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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

KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406)

Barbara Peter1, Emir Hadzijusufovic, Katharina Blatt

  • 1Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Experimental Hematology
|August 6, 2010
PubMed
Abstract

Insights

The multikinase inhibitor INNO-406 effectively targets KIT in certain mastocytosis models but shows resistance with specific KIT mutations. Drug response in neoplastic mast cells depends on the type of KIT mutation present.

Area of Science:

  • Oncology
  • Hematology
  • Pharmacology

Background:

  • Advanced systemic mastocytosis (SM) involves uncontrolled neoplastic mast cell (MC) growth and drug resistance.
  • The tyrosine kinase receptor KIT, often mutated, drives malignant MC proliferation, making it a target for new therapies.

Purpose of the Study:

  • To evaluate the efficacy of the multikinase inhibitor INNO-406 (bafetinib) against neoplastic mast cells.
  • To determine the impact of specific KIT mutations on INNO-406's inhibitory effects in human and canine mastocytosis models.

Main Methods:

  • Assessed INNO-406's effects on primary neoplastic MC, canine mastocytoma cell line C2, and human MC leukemia cell lines HMC-1.1 and HMC-1.2.
  • Analyzed KIT and Lyn phosphorylation and expression in response to INNO-406 treatment.

Main Results:

  • INNO-406 inhibited proliferation in HMC-1.1 cells (KIT V560G) and canine C2 cells (KIT exon 11 ITD) but not in HMC-1.2 cells (KIT V560G/KIT D816V) or KIT D816V-positive SM.
  • INNO-406 blocked KIT phosphorylation in sensitive cell lines but not in resistant ones, while Lyn phosphorylation was inhibited across all tested MC types.
  • Resistance to INNO-406 was observed in human MC with the KIT D816V mutation and in canine MC with a specific exon 11 polymorphism.

Conclusions:

  • INNO-406 primarily targets KIT in neoplastic MC, with efficacy dependent on the specific KIT mutation.
  • The KIT D816V mutation confers resistance in human mastocytosis, while an exon 11 polymorphism may indicate resistance in canine mastocytomas.

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