Dataset Information

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance.

ABSTRACT:

Background

Poly (ADP-ribose) polymerase inhibitors (PARPi) were initially deployed to target breast and ovarian tumors with mutations in DNA damage response genes. Recently, PARPi have been shown to be beneficial in the treatment of prostate cancer (PC) patients having exhausted conventional therapeutics. Despite demonstrating promising response rates, all patients treated with PARPi eventually develop resistance. However, PARPi resistance in PC is not well understood, and further studies are required to understand PARPi resistance in PC to propose strategies to circumvent resistance.

Methods

Starting from well-established olaparib-sensitive PC cell lines (LNCaP, C4-2B and DU145), we derived olaparib-resistant (OR) PC cell lines and performed a microarray analysis.

Results

The olaparib IC50 values of OR cell lines increased significantly as compared to the parental cell lines. Gene expression analyses revealed that different pathways, including DNA repair, cell cycle regulation and autophagy, were affected by acquired resistance. A total of 195 and 87 genes were significantly upregulated and downregulated, respectively, in all three OR cell lines compared to their parental counterparts. Among these genes, we selected BRCC3, ROCK2 and ATG2B for validation. We showed that ROCK2 expression, basal autophagy and homologous recombination (HR) efficiency were increased in all OR cell lines.

Conclusions

Our study provides a new in vitro model to study PARPi resistance in PC and suggests new possible targets to reverse resistance and prolong the benefits of PARPi treatment.

SUBMITTER: Cahuzac M

PROVIDER: S-EPMC9405809 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance.

Cahuzac Maxime M Péant Benjamin B Mes-Masson Anne-Marie AM Saad Fred F

Cancers 20220811 16

<h4>Background</h4>Poly (ADP-ribose) polymerase inhibitors (PARPi) were initially deployed to target breast and ovarian tumors with mutations in DNA damage response genes. Recently, PARPi have been shown to be beneficial in the treatment of prostate cancer (PC) patients having exhausted conventional therapeutics. Despite demonstrating promising response rates, all patients treated with PARPi eventually develop resistance. However, PARPi resistance in PC is not well understood, and further studie ...[more]

PMID: 36010871

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Project description:BackgroundRadiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance.MethodsRadioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Transcriptomic data were also generated for preliminary hypothesis generation involving pathway-focused analyses.ResultsProliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on transcriptomic data they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Radioresistant cell lines derived from ER+ cells also showed a shift from ER to EGFR signalling pathways with increased MAPK and PI3K activity.ConclusionsThis is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.

Dataset Information

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance.

Background

Methods

Results

Conclusions

Publications

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance.

Similar Datasets

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