Abstract
Over half of patients with BRCA1-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCA1-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower simmiparib sensitivity. Additionally, we generated 53BP1−/−/BRCA1−/− clonal variants by the transcription activator-like effector nuclease (TALEN) technique and found that depleting 53BP1 impaired PARP inhibitor sensitivity with a 36.7-fold increase in their IC50 values. Consistent with its effect on PARP inhibitor sensitivity, 53BP1 loss alleviated cell cycle arrest and apoptosis and partially restored HR function. Importantly, 53BP1 depletion dramatically reduced the ability of PARP inhibitors to suppress tumor growth in vivo. The inhibition rate of simmiparib was 74.16% for BRCA1-deficient MDA-MB-436 xenografts, but only 7.79% for 53BP1/BRCA1-deficient xenografts. Re-expressing 53BP1 in the dual-deficient cells restored PARP inhibitor sensitivity and the levels of HR regulators. Considering that at least 10% of BRCA1-deficient breast and ovarian cancers have reduced expression of 53BP1, using a combination of 53BP1 with BRCA1 as a biomarker for patient selection should reduce the number of patients undergoing futile treatment with PARP inhibitors.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No 81573450, 81373446, 81321092, 81603160 and 81402961), the Chinese Academy of Sciences (Hundred Talents Project, XDA12020104, XDA12020205, CASIMM0120152003 and CASIMM0120153005), the Science and Technology Commission of Shanghai Municipality (No 16JC1406300) and the State Key Laboratory of Drug Research (No SIMM1601ZZ-03).
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Supplementary information is available at the website of Acta Pharmacologica Sinica.
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Figure S1
The effect of reduction of PTIP, Rad51 or SMC1 on the sensitivity of BRCA1-deficient MDA-MB-436 cells to the PARP inhibitor simmiparib. (DOCX 92 kb)
Figure S2
Generation of 53BP1/BRCA1 dual-deficient MDA-MB-436 variants. (DOCX 164 kb)
Table S1
The sensitivity of 53BP1-knockout cells to PARP inhibitors in comparison with that of the parental MDA-MB-436 cells. (DOCX 13 kb)
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Yang, Zm., Liao, Xm., Chen, Y. et al. Combining 53BP1 with BRCA1 as a biomarker to predict the sensitivity of poly(ADP-ribose) polymerase (PARP) inhibitors. Acta Pharmacol Sin 38, 1038–1047 (2017). https://doi.org/10.1038/aps.2017.8
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DOI: https://doi.org/10.1038/aps.2017.8
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