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

Abstract

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.