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Transcriptional profiling of EZM8266 treatment in a syngeneic model of PARPi-resistant ovarian cancer.

ABSTRACT: Transcriptional profiling of EZM8266 treatment in a syngeneic model of PARPi-resistant ovarian cancer.

PROVIDER: PRJNA1114461 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29124332_1.fastq.gz	Fastqsanger.gz
	SRR29124332_2.fastq.gz	Fastqsanger.gz
	SRR29124333_1.fastq.gz	Fastqsanger.gz
	SRR29124333_2.fastq.gz	Fastqsanger.gz
	SRR29124334_1.fastq.gz	Fastqsanger.gz

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Project description:We have previously established an in vitro model of PARPi-resistant ovarian cancer by long-term exposure of UWB1.289 ovarian cancer cells (and their isogenic derivatives UWB1.289+BRCA1) to incrementally ascending olaparib concentrations. After finalizing this model, we performed RNA-seq, in order to identify differentially expressed transcript in the PARPi-resistant cells, with a focus on genes related to DNA-repair, multi-drug resistance and EMT. As a result, we show that the phenotype of PARPi resistance is associated with EMT-like traits and up-regulation of selective multi-drug related transcripts.

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Transcriptional profiling of EZM8266 treatment in a syngeneic model of PARPi-resistant ovarian cancer.

Project description:Euchromatin methyltransferase1/2 (EHMT1/2) have been correlated with tumorigenesis and therapy resistance through unknown mechanisms of action. Using a combination of experimental and bioinformatic analyses in several PARP inhibitor resistant ovarian cancer models, we demonstrate that combinatory EHMT and PARP inhibition is effective in treating PARP inhibitor resistant ovarian cancers. Our in vitro studies show that combinatory therapy reactivates transposable elements and increased immunostimulatory dsRNA formation and several immune signaling pathways. Our in vivo studies show that single EHMT and combinatory EHMT and PARP inhibition reduces tumor burden and that this reduction is dependent on CD8 T cells. Together, our results show a direct mechanism by which transposable elements are regulated and how an epigenetic therapy can be used as a fine tune agent to treat cancers with specific genetics.

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Project description:Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Our previous study has demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells, mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, an ALDH1A1 selective inhibitor can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. In order to elucidating the mechanism by which ALDH1A1 renders PARPi resistance to ovarian cancer, we performed RNA-seq analysis to identify genes whose expression can be regulated by ALDH1A1.

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Project description:Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.

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Project description:Background: PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) have known functions in DNA repair and replication, but their expression and activities have not been examined in the context of PARPi-resistant HGSOC. Results: Using mass spectrometry profiling of histone modifications, we observed altered H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance. Conclusions: This study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins such as PCAF, or accessory proteins such as BRPF3, may play a greater role in PARPi response than acetyltransferase functions.

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