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Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors

Monica Ceccon1, Luca Mologni, William Bisson

  • 1Department of Health Sciences, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy. mceccon.manuscript@gmail.com

Molecular Cancer Research : MCR
|December 15, 2012
PubMed

Insights

Crizotinib resistance in anaplastic large cell lymphoma (ALCL) can arise from specific ALK mutations. The L1196Q mutation remains sensitive to other ALK inhibitors, while I1171N confers broad resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Crizotinib, an ALK/MET inhibitor, is approved for ALK+ non-small cell lung cancer (NSCLC) and investigated for other ALK-related diseases.
  • Resistance mutations to tyrosine kinase inhibitors are common, necessitating study in various cancers like anaplastic large cell lymphoma (ALCL).
  • The NPM-ALK fusion protein in ALCL is a potential target for crizotinib therapy.

Purpose of the Study:

  • To investigate crizotinib resistance mechanisms in NPM-ALK+ ALCL cell lines.
  • To identify specific ALK mutations conferring resistance to crizotinib.
  • To evaluate the sensitivity of resistant ALCL cells to other ALK inhibitors.

Main Methods:

  • Selected and characterized two human NPM-ALK+ ALCL cell lines (KARPAS-299, SUP-M2) under crizotinib treatment.
  • Sequenced the ALK kinase domain to identify resistance mutations.
  • Tested crizotinib-resistant cells and Ba/F3 cells expressing mutated NPM-ALK against AP26113 and NVP-TAE684.

Main Results:

  • Crizotinib resistance in KARPAS-299 and SUP-M2 cells was associated with specific ALK mutations: L1196Q and I1171N, respectively.
  • These mutations conferred crizotinib resistance in Ba/F3 cells expressing NPM-ALK.
  • ALK mutations L1196Q conferred sensitivity to AP26113 and NVP-TAE684, whereas I1171N showed cross-resistance to all tested ALK inhibitors.

Conclusions:

  • Identified specific ALK mutations (L1196Q, I1171N) responsible for crizotinib resistance in ALCL.
  • Demonstrated differential sensitivity of these mutations to other ALK inhibitors, highlighting the I1171N mutation's broad resistance profile.
  • Findings offer insights for managing ALCL patients who may relapse after crizotinib treatment.

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