Arsenic compound sensitizes homologous recombination proficient ovarian cancer to PARP inhibitors

AbstractThe poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors show survival benefits in ovarian cancer patients with BRCA1/2 mutation or homologous recombination (HR) deficiency, but only limited efficacy in HR-proficient ones. Another drug, arsenic trioxide (ATO) or arsenic drug (RIF), exerts antitumor effects via inducing DNA damage. Here, we investigated the combined therapeutic effects of the PARP inhibitors and the arsenic compound in HR-proficient ovarian cancer. The combined treatment of niraparib, olaparib, or fluazolepali with ATO showed a significant suppression in tumor cell viability and colony formation. The drug treatment also induced synergistic inhibition of cell proliferation and DNA damage, and acceleration of cell apoptosis in two HR-proficient ovarian cancer cell lines SKOV3 and CAOV3, either by simultaneous or sequential administration. The mechanism underlying these synergistic effects were reflected by the significantly increased ratio of cleaved-PARP/total PARP and decreased ratio of p-AKT/total AKT. Consistently, the combination of olaparib with RIF synergistically reduced the tumor growth in mouse xenograft models. In conclusion, the arsenic compound greatly sensitizes HR-proficient ovarian cancer cells to the PARP inhibitors, and our findings provide an evidence for the clinical treatment development of this combination in HR-proficient ovarian cancer patients.

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Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients

Scientific Reports ◽

10.1038/s41598-019-54116-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Kentaro Sugino ◽

Ryo Tamura ◽

Hirofumi Nakaoka ◽

Nozomi Yachida ◽

Manako Yamaguchi ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Cancer Patients ◽

Somatic Mutations ◽

Clear Cell ◽

Gene Mutations ◽

Parp Inhibitors ◽

Low Grade ◽

Mmr Genes ◽

Selection Of

AbstractWe explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

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Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition

Cell Death and Disease ◽

10.1038/cddis.2017.471 ◽

2017 ◽

Vol 8 (10) ◽

pp. e3070-e3070 ◽

Cited By ~ 22

Author(s):

Dong Hou ◽

Guangwei Xu ◽

Caibo Zhang ◽

Boxuan Li ◽

Junchao Qin ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Cancer Cells ◽

Oxidative Dna Damage ◽

Parp Inhibition ◽

Ovarian Cancer Cells ◽

Homologous Recombination Repair ◽

Recombination Repair ◽

Increased Sensitivity

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PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response

Molecules ◽

10.3390/molecules25246029 ◽

2020 ◽

Vol 25 (24) ◽

pp. 6029

Author(s):

Aladdin Riad ◽

Sarah B. Gitto ◽

Hwan Lee ◽

Harrison D. Winters ◽

Paul M. Martorano ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Cancer Patients ◽

Single Molecule ◽

Single Photon ◽

Ex Vivo ◽

Parp Inhibitor ◽

Adenosine Diphosphate ◽

Ovarian Cancer Cells ◽

Parp 1

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [125I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [123I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.

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Abstract A33: Loss of ZC3H18 disrupts homologous recombination repair and sensitizes ovarian cancer cells to PARP inhibitors and DNA cross-linking agents

10.1158/1557-3265.ovca19-a33 ◽

2020 ◽

Author(s):

Arun Kanakkanthara ◽

Catherine J. Huntoon ◽

Xiaonan Hou ◽

Minzhi Zhang ◽

Ethan P Heinzen ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Cancer Cells ◽

Parp Inhibitors ◽

Ovarian Cancer Cells ◽

Cross Linking ◽

Homologous Recombination Repair ◽

Recombination Repair

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Lymphocyte-specific Protein Tyrosine Kinase Regulates Homologous Recombination (HR) DNA Repair and Targeting Enhances PARPi Utility in HR Proficient Ovarian Cancer

10.1101/2021.03.03.433791 ◽

2021 ◽

Author(s):

Goutam Dey ◽

Rashmi Bharti ◽

Chad Braley ◽

Ravi Alluri ◽

Emily Esakov ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Dna Repair ◽

Homologous Recombination ◽

Tyrosine Kinase ◽

Protein Tyrosine Kinase ◽

Parp Inhibitors ◽

Specific Protein ◽

Brca1 And Brca2 ◽

Nonreceptor Tyrosine Kinase

AbstractPoly-ADP Ribose Polymerase (PARP) inhibitors are clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. PARP targeted therapy has limited efficacy in HR-proficient cancer. In this study, we identified the non-receptor lymphocyte-specific protein tyrosine kinase (LCK) as a novel regulator of HR repair pathways in endometrioid epithelial ovarian cancer (eEOC). Inhibition of LCK attenuates the expression of RAD51, BRCA1, and BRCA2 proteins necessary for HR-mediated DNA repair. HR repair in eEOC cells is LCK dependent. Upon DNA damage LCK expression is increased, and autophosphorylated, activated LCK is localized in the nucleus. LCK inhibition impairs RAD51 foci formation but augments γH2AX formation during DDR indicating reduced ability to repair DNA damage. DNA damage leads to direct interaction of LCK with RAD51 and BRCA1. Finally, attenuation of LCK sensitized HR-proficient eEOC cells to PARP inhibitor. Collectively, the findings identify a mechanism for expanding utility of PARP inhibitors.Graphical AbstractIn BriefDey and colleagues identify the nonreceptor tyrosine kinase LCK as a mediator of homologous recombination directed DNA repair in ovarian cancer. The studies show that LCK inhibition (LCKi) is sufficient to augment Poly (ADP-Ribose) Polymerase inhibitor efficacy in Homologous Recombination (HR) proficient endometrioid ovarian cancer.HighlightsNonreceptor tyrosine kinase LCK regulates expression of HR repair proteins RAD51, BRCA1 and BRCA2.LCKi induces HR deficiency in endometrioid epithelial ovarian cancer.DNA damage leads to autophosphorylation of LCK and co-immunoprecipitation with RAD51 and BRCA1.LCKi potentiates PARP targeted therapy in HR proficient ovarian cancer and expands the utility of the highly successful PARP inhibitors in the clinic.Statement of significanceThis study identifies a novel regulator and signaling pathway for maintaining HR repair during DNA damage. It further demonstrates a new opportunity to increase the utility of PARP inhibitors in HR-proficient eEOC cells.

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LEPTIN PROMOTES A MORE AGGRESIVE BEHAVIOR OF OVARIAN CANCER CELLS: A POTENTIAL EXPLANATION FOR A WORSE PROGNOSIS IN OBESE OVARIAN CANCER PATIENTS: IGCS-0095 Ovarian Cancer

International Journal of Gynecological Cancer ◽

10.1136/00009577-201505001-00052 ◽

2015 ◽

Vol 25 (Supp 1) ◽

pp. 67-67

Author(s):

M. Cuello-Fredes ◽

S. Kato ◽

L. Abarzúa-Catalán ◽

A. Delpiano ◽

C. Trigo ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Ovarian Cancer Cells ◽

Potential Explanation ◽

Worse Prognosis

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Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy

International Journal of Molecular Sciences ◽

10.3390/ijms22084203 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4203

Author(s):

Giorgio Valabrega ◽

Giulia Scotto ◽

Valentina Tuninetti ◽

Arianna Pani ◽

Francesco Scaglione

Keyword(s):

Ovarian Cancer ◽

Signal Transduction ◽

Dna Damage ◽

Chemical Structure ◽

Parp Inhibitors ◽

Mechanisms Of Action ◽

Point Of View ◽

Safety And Efficacy ◽

Damage Repair ◽

Pharmacokinetic Properties

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.

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Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

Cells ◽

10.3390/cells10010130 ◽

2021 ◽

Vol 10 (1) ◽

pp. 130

Author(s):

Michal Kielbik ◽

Izabela Szulc-Kielbik ◽

Magdalena Klink

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Cancer Patients ◽

Tumor Cells ◽

Cytotoxic T Cells ◽

Adaptive Immune Response ◽

Ovarian Cancer Cells ◽

Immunogenic Cell Death ◽

Antigen Presenting ◽

Molecular Patterns

Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.

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