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Targeting the insulin-like growth factor-1 receptor to overcome imatinib resistance in chronic myeloid leukemia

Seiichi Okabe1, Yuya Arai2, Akihiko Gotoh2

  • 1Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan. okabe@tokyo-med.ac.jp.

Discover Oncology
|December 24, 2024
PubMed

Insights

The insulin-like growth factor 1 (IGF-1) pathway contributes to imatinib resistance in chronic myeloid leukemia (CML). Inhibiting the IGF-1 receptor (IGF-1R) with linsitinib shows promise for overcoming this resistance in CML patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Chronic myeloid leukemia (CML) patients often develop resistance to imatinib therapy.
  • The insulin-like growth factor 1 (IGF-1) signaling pathway is implicated in various cancers and may play a role in CML treatment resistance.

Purpose of the Study:

  • To investigate the role of the IGF-1 signaling pathway in CML and imatinib resistance.
  • To evaluate the efficacy of linsitinib, an IGF-1 receptor (IGF-1R) inhibitor, in preclinical CML models.

Main Methods:

  • Analysis of IGF-1 gene expression in CML patient data.
  • Assessment of linsitinib's effect on CML cell lines, including imatinib-resistant ones.
  • Evaluation of combined imatinib and linsitinib treatment.
  • Silencing of IGF-1R using small interfering ribonucleic acid (siRNA).

Main Results:

  • Elevated IGF-1 binding proteins and upregulated IGF-1-related genes were observed in CML patients, particularly those resistant to imatinib.
  • Linsitinib significantly reduced cell viability and increased cytotoxicity in CML cell lines, including imatinib-resistant lines.
  • Combination therapy with imatinib and linsitinib enhanced anti-leukemic effects, and IGF-1R silencing sensitized cells to imatinib.

Conclusions:

  • The IGF-1 signaling pathway is involved in imatinib resistance in CML.
  • IGF-1R inhibition, using agents like linsitinib, represents a potential strategy to overcome imatinib resistance.
  • Targeting IGF-1R may improve treatment outcomes for patients with imatinib-resistant CML.
Keywords:
Chronic myeloid leukemiaImatinib resistanceInsulin-like growth factor -1 receptor inhibitor

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