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- W2886505839 abstract "e13564 Background: With the recent success of poly (ADP-ribose) polymerase inhibitor (PARPi) in the treatment of BRCA1 or BRCA2 mutated cancers, there is increasing interest to explore synthetic lethality in cancers with defective DNA repair pathways. Rad51 is an essential protein in the homologous recombination repair (HRR) of DNA double strand breaks. Previous studies with non metastatic prostate cancer (mCaP) cells have reported low Rad51 levels in cells with loss of PTEN or under hypoxia, which then led to their sensitivity to PARPi. Given intra tumor hypoxia and loss of PTEN is common in mCaP, we test PAPRi, ABT888 and DNA damaging topoisomerase I inhibitor, CPT11, either alone or in combination in mCaP preclinical models. Methods: mCaP cell lines with functional PTEN (DU145) and loss of PTEN (PC3) were grew under normoxia (21% O2) or hypoxia (0.2% O2). DNA damage, HRR, apoptosis were assessed with comet assay, western blot, immunofluorescence and flowcytometry. The regulation of RAD51 was studied with quantitative RT-PCR and RAD51 promoter reporter assay. PC3 xenograft was used for in vivo study. Results: Despite of its low levels of expression under hypoxia, up regulation of Rad51 was observed soon after treating hypoxic PC3 and Du145 cells with ABT888 or SN38, an active metabolite of CPT11. Such Rad51 up regulation led to less DNA damage and apoptosis under hypoxia compared to normoxia. Inhibiting RAD51 expression with siRNA overcame PC3 and Du145’s resistance to SN38. Furthermore, ABT888 enhanced the activities of SN38 as detected by clonogenic assay and flowcytometry under both normoxia and hypoxia. Consistent with the in vitro data, ABT888 by itself had limited anti-tumor activities despite the loss of PTEN in PC3 xenografts. The anti-tumor activity of single agent CPT11 was significantly improved with the ABT888 and CPT11 combination (P<0.008). Conclusions: neither loss of PTEN nor hypoxia sensitized mCaP cells to PARPi or DNA damaging drugs. Such resistance under hypoxia was at least partly due to up regulation of Rad51. Combining ABT888 with CPT11 overcame the resistance to CPT11 under hypoxia and enhanced its anti-tumor activities both in vitro and in vivo." @default.
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- W2886505839 date "2012-05-20" @default.
- W2886505839 modified "2023-09-27" @default.
- W2886505839 title "The roles of hypoxia, PTEN, and Rad51 in mediating metastatic prostate cancer cells' responses to PARP inhibitor and topoisomerase 1 inhibitor." @default.
- W2886505839 doi "https://doi.org/10.1200/jco.2012.30.15_suppl.e13564" @default.
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