Suppression of homologous recombination sensitizes human tumor cells to IGF-1R inhibition.
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 γH2AX 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(-/-) colorectal cancer cells, compared with isogenic BRCA2(+/-) cells. We also assessed chemical HR inhibitors, finding that RAD51 inhibitor 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 GI50 and 13-fold reduction in GI80. 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.
Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, United Kingdom.
Kunal A
KA
Lodhia
Shan
S
Gao
Tamara
T
Aleksic
Fumiko
F
Esashi
Valentine M
VM
Macaulay
D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
C562081:AZ 12253801; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D001896:Boron Compounds; C468783:H2AX protein, human; D006657:Histones; D007555:Isoxazoles; D011743:Pyrimidines; D011804:Quinolines; C512984:RO 3306; D013844:Thiazoles; C042168:boron oxide; D017526:Receptor, IGF Type 1; D016203:CDC2 Protein Kinase; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
BRCA2; DNA repair; IGF-1R inhibitor; RAD51; biomarker; homologous recombination; type 1 IGF receptor