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

The insulin-like growth factor (IGF) axis regulates cancer cell proliferation, growth, invasion, and therapy resistance. Elevated expression of the type 1 IGF receptor (IGF-1R) is linked to radioresistance and biochemical recurrence in prostate cancer, yet the molecular mechanisms underlying IGF-1R-mediated DNA damage responses remain unclear. We investigated the role of IGF-1R in DNA double-strand break (DSB) repair by assessing chromatin recruitment of DNA repair proteins, repair pathway usage, and therapeutic sensitivity in cancer cell models with altered IGF-1R status. Loss of IGF-1R impaired DNA-dependent protein kinase catalytic subunit (DNA-PKcs) localisation to chromatin, resulting in defective non-homologous end-joining (NHEJ) and a compensatory reliance on alternative repair pathways, including microhomology-mediated end-joining (MMEJ). Modulating IGF-1R expression restored radiosensitivity in poly (ADP-ribose) polymerase (PARP) inhibitor-resistant breast cancer cells. IGF-1R inhibition compromises canonical DSB repair and re-sensitises resistant cancer cells to therapy, supporting its potential as a therapeutic strategy in homologous recombination-deficient tumours. Furthermore, IGF-1R mutant cancers may benefit from targeted inhibition of the MMEJ pathway.