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Updated: Jan 23, 2026

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LIN28A-Dependent Kinome and Phosphoproteome Reprogramming Promotes Imatinib Resistance

Owen F J Hovey1, Mallory I Frederick1, Quan M Quach1

  • 1Department of Biochemistry, Western University, London, Ontario, Canada.

Molecular & Cellular Proteomics : MCP
|January 21, 2026
PubMed

Insights

LIN28A, a protein overexpressed in imatinib-resistant chronic myeloid leukemia (CML), drives resistance by coordinating kinase networks. Targeting LIN28A or its downstream kinases, like PKC, can overcome resistance to BCR-ABL tyrosine kinase inhibitors (TKIs).

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Resistance to BCR-ABL tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) is a significant clinical challenge.
  • Mechanisms of TKI resistance include BCR-ABL kinase domain mutations, gene amplification, and kinase-independent pathways.
  • Understanding novel resistance mediators is crucial for developing effective CML therapies.

Purpose of the Study:

  • To investigate the proteomic and phosphoproteomic changes associated with imatinib resistance in CML.
  • To identify novel molecular targets that mediate resistance to BCR-ABL TKIs.
  • To explore therapeutic strategies for overcoming TKI resistance in CML.

Main Methods:

  • Quantitative mass spectrometry was used to compare the proteome and phosphoproteome of imatinib-sensitive (K562) and imatinib-resistant (ImR) CML cells.
  • RNA interference (shRNA) was employed to deplete LIN28A expression.
  • Ectopic expression of LIN28A was performed in parental K562 cells.
  • Pharmacological inhibitors targeting LIN28A-dependent kinases were utilized.

Main Results:

  • LIN28A was identified as a critical mediator of imatinib resistance, significantly overexpressed and hyperphosphorylated in ImR cells.
  • Depletion of LIN28A restored imatinib sensitivity, while its ectopic expression induced resistance.
  • LIN28A coordinates a kinase-substrate network regulating proliferation, survival, and metabolism, driving resistance.
  • Pharmacological inhibition of LIN28A-dependent kinases (PKC, AKT, SGK1, RPS6K) suppressed ImR cell proliferation.
  • Midostaurin, a PKC/FLT3 inhibitor, re-sensitized ImR cells to imatinib.

Conclusions:

  • LIN28A is a key driver of imatinib resistance in CML, acting through extensive kinase signaling networks.
  • Targeting LIN28A and its downstream effectors, particularly protein kinase C (PKC), represents a promising strategy to overcome resistance to BCR-ABL TKIs.
  • Midostaurin shows potential in combination therapy to re-sensitize CML cells to imatinib and next-generation TKIs.
Keywords:
AKT/mTOR signallingLIN28Achronic myeloid leukemiaimatinib resistancekinome reprograming

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