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Area of Science:

  • Molecular Biology
  • Cancer Biology
  • DNA Damage and Repair

Background:

  • Insulin-like growth factor 1 receptor (IGF1R) inhibition delays DNA repair.
  • The role of IGF1R in endogenous DNA damage and replication stress is unclear.

Purpose of the Study:

  • To investigate the role of IGF1R in endogenous DNA damage and replication.
  • To identify therapeutic strategies targeting IGF1R in cancer.

Main Methods:

  • Inhibition and depletion of IGF1R in cancer cells and fibroblasts.
  • Analysis of DNA lesions, replication fork progression, and cell signaling (ATR-CHK1, AKT, MEK/ERK, JUN).
  • Assessment of ribonucleotide reductase (RNR) subunit RRM2 expression and function.
  • Compound screens to identify synergistic drug combinations.
  • Evaluation of tumor growth in ATM-proficient and ATM-null xenografts.

Main Results:

  • IGF1R inhibition induces endogenous DNA lesions and replication stress, characterized by delayed fork progression and intra-S-phase checkpoint activation.
  • IGF1R regulates RRM2 expression via AKT, MEK/ERK, and JUN, impacting dNTP supply and RNR function.
  • RRM2 overexpression rescues the replication stress phenotype caused by IGF1R inhibition.
  • IGF1R inhibition exhibits synthetic lethality with ATM loss, selectively compromising ATM-null cancer cell growth and xenograft regression.
  • This synthetic lethality arises from the conversion of single-stranded lesions into toxic double-strand breaks in ATM-deficient cells upon IGF inhibition.

Conclusions:

  • IGF1R plays a critical role in alleviating replication stress by regulating RNR function and dNTP supply.
  • IGF1R blockade induces replication stress and establishes a reciprocal codependence on ATM.
  • The identified IGF:ATM codependence provides a potential therapeutic strategy for ATM-deficient cancers.