Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

Summey, Rebekah; Uyar, Denise

doi:10.20517/cdr.2021.146

Cited by 8 publications

(6 citation statements)

References 61 publications

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“…Platinum resistance is a strong predictive marker for PARPi resistance, indicating inter-related mechanisms ( 2 , 3 , 42 ). Indeed, the platinum-resistant cell line used in this study (A2780cis) also demonstrated PARPi resistance relative to its parental cell line.…”

Section: Discussionmentioning

confidence: 99%

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Berckmans,

Ene,

Ben-Meir

et al. 2024

Front. Oncol.

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BackgroundOvarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models.MethodsA2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed.ResultsThe nature of TTFields-drug interaction was dependent on the drug’s underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.ConclusionBy inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Berckmans,

Ene,

Ben-Meir

et al. 2024

Front. Oncol.

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“…The low survival rate and high mortality rate of OC are multifactorial, poor chemotherapy response and a high proportion of drug resistance had been considered as the most significant contributors. Related studies suggest that aberrant expression of resistance‐related genes is an important and universal cause of resistance 3–6 . Therefore, the mining of drug resistance genes in OC is important to improve the chemotherapy effect.…”

Section: Introductionmentioning

confidence: 99%

“…Related studies suggest that aberrant expression of resistance‐related genes is an important and universal cause of resistance. 3 , 4 , 5 , 6 Therefore, the mining of drug resistance genes in OC is important to improve the chemotherapy effect.…”

Section: Introductionmentioning

confidence: 99%

Expression of human dCTP pyrophosphatase 1 (DCTPP1) and its association with cisplatin resistance characteristics in ovarian cancer

Wang,

Chen,

Chen

et al. 2024

J Cellular Molecular Medi

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Cisplatin (DDP) resistance is a major challenge in treating ovarian cancer patients. A recently discovered enzyme called dCTP pyrophosphatase 1 (DCTPP1) has been implicated in regulating cancer characteristics, including drug responses. In this study, we aimed to understand the role of DCTPP1 in cancer progression and cisplatin response. Using publicly available databases, we analysed the expression and clinical significance of DCTPP1 in ovarian cancer. Our bioinformatics analysis confirmed that DCTPP1 is significantly overexpressed in ovarian cancer and is closely associated with tumour progression and poor prognosis after cisplatin treatment. We also found that DCTPP1 located in oxidoreductase complex and may be involved in various biological processes related to cisplatin resistance, including pyrimidine nucleotide metabolism, the P53 signalling pathway and cell cycle signalling pathways. We observed higher expression of DCTPP1 in cisplatin‐resistant cells (SKOV3/DDP) and samples compared to their sensitive counterparts. Additionally, we found that DCTPP1 expression was only enhanced in SKOV3/S cells when treated with cisplatin, indicating different expression patterns of DCTPP1 in cisplatin‐sensitive and cisplatin‐resistant cancer cells. Our study further supports the notion that cisplatin induces intracellular reactive oxygen species (ROS) and triggers cancer cell death through excessive oxidative stress. Knocking out DCTPP1 reversed the drug resistance of ovarian cancer cells by enhancing the intracellular antioxidant stress response and accumulating ROS. Based on our research findings, we conclude that DCTPP1 has prognostic value for ovarian cancer patients, and targeting DCTPP1 may be clinically significant in overcoming cisplatin resistance in ovarian cancer.

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“…In recent years, maintenance therapies including poly (ADP-ribose) polymerase inhibitors (PARPi), have become a valuable addition in patients with somatic or germline BRCA1/2 tumors or homologous recombination deficiency (HRD), (3)(4)(5)(6). Despite these therapeutic advancements, most patients with metastatic HGSOC inevitably experience disease recurrence and ultimately platinum-resistance disease (7). Considering these challenges, the necessity for overcoming drug resistance remains a critical clinical priority for these patients.…”

Section: Introductionmentioning

confidence: 99%

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Coelho,

Seashore-Ludlow,

Schütz

et al. 2024

Preprint

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Resistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin's pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin's therapeutic impact. We observed enhanced cell death in low mesothelin expressing cancer cells when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy in ex vivo patient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNF alpha signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNF alpha-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy.

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Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

Cited by 8 publications

References 61 publications

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Expression of human dCTP pyrophosphatase 1 (DCTPP1) and its association with cisplatin resistance characteristics in ovarian cancer

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

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