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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

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Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors

Lorraine Springuel1, Tekla Hornakova1, Elisabeth Losdyck1

  • 1Ludwig Institute for Cancer Research, Brussels Branch, Belgium; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;

Blood
|October 30, 2014
PubMed

Insights

Cancer cells gain self-sufficiency through Janus kinase (JAK) mutations. Co-activating JAK1 and JAK3 mutations drive T-cell transformation and lead to resistance against JAK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Cancer cells acquire growth signal self-sufficiency, a key hallmark of cancer.
  • The TS1 cell line, dependent on interleukin-9, develops growth factor independence via Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation.

Purpose of the Study:

  • To investigate the genetic basis of growth factor independence in TS1 cells.
  • To elucidate the role of Janus kinase (JAK) mutations in T-cell transformation.
  • To understand the mechanisms of resistance to JAK inhibitors.

Main Methods:

  • Analysis of TS1 cell line clones for mutations in JAK1 and JAK3.
  • Transient and stable expression of JAK1 and JAK3 mutants.
  • Assessment of STAT activation.
  • Short-term and long-term culture assays with JAK inhibitors (ruxolitinib, CMP6).

Main Results:

  • Activating mutations in JAK1, JAK3, or both were identified as the cause of transforming events.
  • JAK1 and/or JAK3 mutants induce STAT activation, with coexpression leading to enhanced activation.
  • JAK inhibitors blocked proliferation in short-term assays, but resistance emerged in long-term cultures.
  • Resistance to CMP6 was mediated by acquiring secondary activating mutations in the other JAK kinase (JAK1 or JAK3), not in the ATP-binding pocket.

Conclusions:

  • Cooperation between JAK1 and JAK3 mutations drives T-cell transformation and growth factor independence.
  • A novel mechanism of resistance to JAK inhibitors involves acquiring mutations in complementary JAK kinases.
  • These findings highlight the complex interplay of JAK kinases in cancer development and drug resistance.

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