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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

Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase

Sara Redaelli1, Luca Mologni, Roberta Rostagno

  • 1Department of Clinical Medicine and Prevention, University of Milano-Bicocca, S. Gerardo Hospital, Monza, Milan, Italy. sara.redaelli@unimib.it

American Journal of Hematology
|October 10, 2012
PubMed

Insights

Three new BCR/ABL mutations (L248R, T315V, F317R) were identified in leukemia patients. DCC-2036 showed sensitivity to L248R and T315V mutations, offering new hope for drug-resistant chronic myeloid leukemia (CML) treatment.

Area of Science:

  • Oncology
  • Hematology
  • Molecular Biology

Background:

  • BCR/ABL kinase domain (KD) mutations are a primary cause of resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML).
  • These mutations can disrupt TKI binding, leading to treatment failure.
  • Understanding novel mutations and their resistance profiles is crucial for effective CML management.

Purpose of the Study:

  • To identify and characterize new BCR/ABL mutations.
  • To evaluate the efficacy of existing and novel TKIs against these mutations.
  • To provide a resistance profile for guiding treatment decisions in TKI-resistant CML.

Main Methods:

  • Discovery of three novel BCR/ABL mutations (L248R, T315V, F317R) in CML and Ph+ ALL patients.
  • Screening of mutations against second-generation (bosutinib, nilotinib, dasatinib) and third-generation TKIs (ponatinib, DCC-2036).
  • Calculation of IC50 values and relative resistance (RR) to categorize resistance levels (sensitive, moderately resistant, resistant, highly resistant).

Main Results:

  • L248R and T315V mutations exhibited high resistance to imatinib, bosutinib, dasatinib, and nilotinib, with intermediate resistance to ponatinib, but remained sensitive to DCC-2036.
  • F317R mutation showed moderate resistance to imatinib and nilotinib, and resistance/high resistance to dasatinib, bosutinib, ponatinib, and DCC-2036.
  • Defined four resistance levels based on RR values to classify TKI efficacy against specific BCR/ABL mutants.

Conclusions:

  • Novel BCR/ABL mutations L248R, T315V, and F317R contribute to TKI resistance in CML and Ph+ ALL.
  • DCC-2036 demonstrates significant activity against L248R and T315V mutations, offering a potential therapeutic option.
  • Comprehensive drug activity profiles against BCR/ABL mutants are valuable for clinical decision-making in managing drug-resistant leukemia.

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