Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

Abstract

Inhibition of type 1 IGF receptor (IGF-1R) sensitizes to DNA-damaging cancer treatments, and delays repair of DNA double strand breaks (DSBs) by non-homologous end-joining and homologous recombination (HR). In a recent screen for mediators of resistance to IGF-1R inhibitor AZ12253801, we identified RAD51, required for the strand invasion step of HR. These findings prompted us to test the hypothesis that IGF-1R-inhibited cells accumulate DSBs formed at endogenous DNA lesions, and depend on residual HR for their repair. Indeed, initial experiments showed time-dependent accumulation of cH2AX foci in IGF-1R -inhibited or -depleted prostate cancer cells. We then tested effects of suppressing HR, and found that RAD51 depletion enhanced AZ12253801 sensitivity in PTEN wild-type prostate cancer cells but not in cells lacking functional PTEN. Similar sensitization was induced in prostate cancer cells by depletion of BRCA2, required for RAD51 loading onto DNA, and in BRCA2 2/2 colorectal cancer cells, compared with isogenic BRCA21/2 cells. We also assessed chemical HR inhibitors, finding that RAD51inhibitor BO2 blocked RAD51 focus formation and sensitized to AZ12253801. Finally, we tested CDK1 inhibitor RO-3306, which impairs HR by inhibiting CDK1-mediated BRCA1 phosphorylation. R0-3306 suppressed RAD51 focus formation consistent with HR attenuation, and sensitized prostate cancer cells to IGF-1R inhibition, with 2.4-fold reduction in AZ12253801 GI 50 and 13-fold reduction in GI 80 . These data suggest that responses to IGF-1R inhibition are enhanced by genetic and chemical approaches to suppress HR, defining a population of cancers (PTEN wild-type, BRCA mutant) that may be intrinsically sensitive to IGF-1R inhibitory drugs.

The impact of the IGF-1 system of cancer cells on radiation response – An in vitro study

“…BRCA2 is a key mediator of repair by homologous recombination (HRR) and recruits RAD51 to the DNA damage site: cells that express defective BRCA2 are unable to form RAD51 foci after irradiation [44] . Previous reports have demonstrated that depletion of BRCA2 sensitizes cells to IGF-1R inhibition and that RAD51 foci formation is reduced, indicating defective HRR [45] . BRCA2 undergoes epistatic interactions with four RAD51 paralogs, and its loss alone can affect the HRR [46] .…”

Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors

“…Despite the strong rationale around IGF-1R pathway inhibition, the promising preclinical data and its reasonable tolerability, the clinical efficacy has been disappointing [ 49 , 50 ]. Our study shows that cells with HR deficiency are more sensitive to IGF-1Rki, suggesting that this subset of patients could benefit from this targeted therapy.…”

The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

“…Traditional chemotherapy, in particular platinum-based compounds, targets rapidly dividing cells primarily by inducing DNA damage. Pre-clinical studies suggest IR/IGF-IR signaling protects cells from DNA damage and induces DNA damage repair via non-homologous end joining (NHEJ) and homologous repair ( 129 , 130 ). Consistent with this, inhibition of IGF-IR causes sensitization to cisplatin ( 98 , 131 , 132 ), doxorubicin, and trabectedin ( 133 ), as well as ionizing radiation ( 129 , 134 – 136 ) in ovarian, prostate, colon, and breast cancer cells and in mouse xenograft models.…”