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Published on: August 21, 2021

Loss of IGF-1R impairs DNA-PKcs recruitment to chromatin leading to defective end-joining

Matthew O Ellis1,2,3, Jack V Mills2, Wojciech Niedzwiedz3

  • 1UK-DRI, Department of Clinical Neuroscience, University of Cambridge, Cambridge, England.

Molecular Oncology
|May 7, 2026
PubMed

Insights

The insulin-like growth factor 1 receptor (IGF-1R) impacts DNA repair, affecting cancer cell therapy resistance. Inhibiting IGF-1R can re-sensitize resistant cancers to treatments like PARP inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The insulin-like growth factor (IGF) axis is crucial in cancer progression and therapy resistance.
  • Elevated type 1 IGF receptor (IGF-1R) expression correlates with radioresistance and recurrence in prostate cancer.
  • Mechanisms of IGF-1R in DNA double-strand break (DSB) repair are not fully understood.

Purpose of the Study:

  • To investigate the role of IGF-1R in DNA DSB repair pathways.
  • To assess the impact of IGF-1R on DNA repair protein recruitment and cancer cell sensitivity to therapy.

Main Methods:

  • Examined chromatin recruitment of DNA repair proteins in cancer cell models with varying IGF-1R levels.
  • Assessed DNA repair pathway usage and therapeutic sensitivity.
  • Utilized poly (ADP-ribose) polymerase (PARP) inhibitor-resistant breast cancer cells.

Main Results:

  • Loss of IGF-1R impaired DNA-dependent protein kinase catalytic subunit (DNA-PKcs) chromatin localization, hindering non-homologous end-joining (NHEJ).
  • Cancer cells showed compensatory reliance on alternative repair pathways like microhomology-mediated end-joining (MMEJ).
  • Modulating IGF-1R restored radiosensitivity in PARP inhibitor-resistant breast cancer cells.

Conclusions:

  • IGF-1R inhibition disrupts canonical DSB repair, re-sensitizing resistant cancer cells to therapy.
  • IGF-1R is a potential therapeutic target, especially in homologous recombination-deficient tumors.
  • Targeting MMEJ may benefit cancers with IGF-1R mutations.
Keywords:
DNA repairIGF‐1RIrradiationprostate cancer

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