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IGF receptor (IGF-1R) inhibition delays repair of radiation-induced DNA double-strand breaks (DSBs), prompting us to investigate whether IGF-1R influences endogenous DNA damage. Here, we demonstrate that IGF-1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. We detect delayed replication fork progression in IGF-inhibited or IGF-1R depleted cancer cells, accompanied by activation of ATR-CHK1 signaling and the intra-S-phase checkpoint. We show that this phenotype reflects unanticipated regulation of global replication by IGF-1, mediated via AKT, MEK/ERK and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. Consequently, IGF-1R inhibition or depletion downregulate RRM2, compromising RNR function and perturbing dNTP supply. We show that the resulting delay in fork progression and hallmarks of replication stress are rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF-1 regulates replication. Suspecting existence of a backup pathway protecting from toxic sequelae of replication stress, we performed targeted compound screens in breast cancer cells and identify synergy between IGF inhibition and ATM loss. Reciprocal screens of ATM proficient/deficient fibroblasts identified an IGF-1R inhibitor as the top hit. We find that IGF inhibition selectively compromises growth of ATM null cells and spheroids, and causes regression of ATM null xenografts. Finally, we show that this synthetic lethal effect reflects conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. These data implicate IGF-1R in alleviating replication stress, and the reciprocal IGF:ATM codependence we identify provides an approach to exploit this effect in ATM-deficient cancers.


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