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MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC.

ABSTRACT: BACKGROUND:PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. METHODS:We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. RESULTS:High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P?

SUBMITTER: Sun C

PROVIDER: S-EPMC6995078 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC.

Sun Chenggong C Cao Wenyu W Qiu Chunping C Li Chengcheng C Dongol Samina S Zhang Zhiwei Z Dong Ruifen R Song Kun K Yang Xingsheng X Zhang Qing Q Kong Beihua B

Journal of hematology & oncology 20200131 1

<h4>Background</h4>PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies.<h4>Methods</h4>We probed two da ...[more]

PMID: 32005272

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Project description:Objective: Patients initially sensitive to PARPi (PARP inhibitor) regain resistance because of homologous recombination (HR) restoration, although PARPi has a synthetic lethality effect on serous ovarian cancer cells with BRCA1/2 mutations. This study aimed to investigate the role of NEAT1 in HR function and whether targeting NEAT1 in serous ovarian cancer cells could increase PARPi sensitivity. Methods: Ovarian cancer patients' clinical information and the expression of NEAT1 were collected from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Ovarian cancer (OC) cells HeyA8 and SKOV3 were silenced by transfecting NEAT1 ASO. QRT-PCR confirmed the mRNA expression of RAD51, FOXM1, NEAT1_1 and NEAT1_2. We assessed the expression of RAD51, FOXM1, and γ-H2AX by Western blotting and Immunofluorescence. Comet Assays were used to detect DNA double-strand damage levels. In OC cells transfected with NEAT1 ASO or co-transfected overexpression RAD51/empty vector and si-NEAT1/si-ctrl, the sensitivity to Olaparib was determined using CCK8 assay. The Kaplan-Meier survival curves assessed the prognostic and predictive roles of NEAT1 in OC. Results: NEAT1 was an independent prognostic marker of ovarian cancer. NEAT1 knockdown reduced the expression of NEAT1_1, NEAT1_2, RAD51, and FOXM1 and increased the expression of γ-H2AX. In addition, Olaparib increased the expression of RAD51, representing HR repair efficiency, which was inhibited by NEAT1 knockdown. Moreover, the knockdown of NEAT1 increased the DNA damage caused by Olaparib, demonstrated by increased nuclear γ-H2AX foci, DNA in the tail, and expression of γ-H2AX. NEAT1 knockdown sensitized ovarian cancer cells to Olaparib by targeting RAD51-HR. NEAT1 expression could predict response to chemotherapy for ovarian cancer. Conclusions: NEAT1 knockdown inhibited HR capacity and increased DNA damage caused by Olaparib in serous ovarian cancer cells, making them more sensitive to Olaparib and providing a crucial therapeutic advantage of increasing sensitivity to Olaparib.

Project description:Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802, we have discovered that regorafenib can be safely combined with the phosphodiesterase 5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS downregulating drug neratinib, could enhance the lethality of [regorafenib + sildenafil]. Neratinib enhanced [regorafenib + sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K-RAS and of multiple histone deacetylase (HDAC) proteins that required autophagosome formation. It caused green fluorescent protein or red fluorescent protein-tagged forms of K-RAS V12 to localize into large intracellular vesicles. Compared with [regorafenib + sildenafil], the three-drug combination caused greater and more prolonged activation of the ATM-AMPK-ULK-1 pathway and caused a greater suppression and prolonged inactivation of mammalian target of rapamycin, AKT, and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ataxia-telangiectasia-mutated (ATM)-AMP-dependent protein kinase (AMPK) signaling whereas knockdown of Beclin1, ATG5, FADD, and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib + sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers programmed death-ligand 1, ornithine decarboxylase, and indoleamine 2,3-dioxygenase-1 and increased the expression of major histocompatibility complex A (MHCA), which also required autophagosome formation. Knockdown of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.

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MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC.

Publications

MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC.

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