Dataset Information

Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer.

ABSTRACT: Due to its regulation of CDK1/2 phosphorylation, WEE1 plays essentially roles in the regulations of G2/M checkpoint and DNA damage response (DDR). WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents. We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. Typically, PARP inhibitors are effective in germline BRCA 1/2 mutated breast and ovarian cancer, but their applicabilities in triple-negative breast cancer (TNBC) are limited. This study was conducted to investigate the anti-tumor effects of the WEE1 inhibitor, AZD1775, and the mechanism responsible for its potentiation of sensitivity to olaparib (a PARP inhibitor) via the modulation of DDR in TNBC cells. Our results suggest that AZD1775 could be used to broaden the application range of olaparib in TNBC and provide a rationale for a clinical trial of combined olaparib and AZD1775 therapy.

SUBMITTER: Ha DH

PROVIDER: S-EPMC7303169 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer.

Ha Dong-Hyeon DH Min Ahrum A Kim Seongyeong S Jang Hyemin H Kim So Hyeon SH Kim Hee-Jun HJ Ryu Han Suk HS Ku Ja-Lok JL Lee Kyung-Hun KH Im Seock-Ah SA

Scientific reports 20200618 1

Due to its regulation of CDK1/2 phosphorylation, WEE1 plays essentially roles in the regulations of G2/M checkpoint and DNA damage response (DDR). WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents. We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. Typically, PARP ...[more]

PMID: 32555285

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Project description:Poly-(ADP)-ribose polymerase inhibitors (PARPi) and platinum-based drugs are promising therapies for triple negative breast cancers (TNBC) with BRCA1 or BRCA2 loss. PARPi(s) show better efficacies when combined with platinum-based therapy, however, acquisition of PARPi resistance has been linked with co-resistance to platinum-based drugs. Here, we show that TNBCs with constitutively hyperactivated PARP-1 display greater tolerances for the PARPi olaparib and cisplatin, and respond synergistically to olaparib/cisplatin combinations with increased cytotoxicity. Regardless of BRCA1 and PARP-1 activity status, upon gaining olaparib resistance (OlaR), OlaR MDA-MB-468 (BRCA1 wild-type) and SUM1315 (BRCA1 mutant) TNBC cells retain cisplatin sensitivities of their isogenic parental counterparts. OlaR TNBC cells express decreased levels of PARP-1 and Pol η, a translesion-synthesis polymerase important in platinum-induced interstrand crosslink repair. Although native RAD51 recombinase levels are unaffected, anti-RAD51 immunoreactive low molecular weight sbands are exclusively detected in OlaR cells. Despite normal BRCA1, RAD51 foci formation/recruitment to double-strand breaks are impaired in OlaR MDA-MB-468 cells, suggesting homologous-recombination impairment. RNA-seq and pathway analysis of cisplatin-affected genes revealed enrichment of G2/M cell cycle regulation and DNA repair pathways in parental and OlaR MDA-MB-468 cells whereas parental and OlaR SUM1315 cells showed enrichment of inflammatory stress response pathways associated with TNFR1/2, TWEAK and IL-17 signaling. These data show that TNBC models with wild type versus mutant BRCA1 exhibit differences in CDDP-induced cellular response pathways, however, the CDDP-induced signaling responses remain stable across the isogenic models of OlaR from the same lineage. These data also show that adaptive OlaR does not automatically promote cisplatin resistance, implicating the potential benefit of platinum-based therapy for OlaR TNBCs.

Dataset Information

Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer.

Publications

Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer.

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