Abstract 267: Targeting the alt-NHEJ DNA repair pathway selectively sensitizes KRAS-mutant cancer cells to chemotherapy

2019 ◽  
Author(s):  
Patricia S. Haehnel ◽  
Sarah Swoboda ◽  
Nadine Lehmann ◽  
Sebastian Rosigkeit ◽  
Hernike Gothe ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Repair Pathway

scholarly journals MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

2019 ◽  
Vol 116 (35) ◽  
pp. 17438-17443 ◽  
Author(s):  
Gayathri Srinivasan ◽  
Elizabeth A. Williamson ◽  
Kimi Kong ◽  
Aruna S. Jaiswal ◽  
Guangcun Huang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Negative Regulator ◽  
Nonhomologous End Joining ◽  
Chromosomal Translocations ◽  
Replication Forks ◽  
Repair Pathway ◽  
End Joining ◽  
Parp1 Inhibitors

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

Abstract 267: Targeting the alt-NHEJ DNA repair pathway selectively sensitizes KRAS-mutant cancer cells to chemotherapy

2019 ◽  
Author(s):  
Patricia S. Haehnel ◽  
Sarah Swoboda ◽  
Nadine Lehmann ◽  
Sebastian Rosigkeit ◽  
Hernike Gothe ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Repair Pathway

scholarly journals Valproic acid causes radiosensitivity of breast cancer cells via disrupting the DNA repair pathway

2016 ◽  
Vol 5 (3) ◽  
pp. 859-870 ◽  
Author(s):  
Yue Luo ◽  
Hui Wang ◽  
Xipeng Zhao ◽  
Chao Dong ◽  
Fengmei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Valproic Acid ◽  
Dna Repair ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Breast Cancer Cells ◽  
Histone Deacetylase Inhibitors ◽  
Clinical Treatment ◽  
Repair Pathway ◽  
Treatment Of Epilepsy

Valproic acid (VPA) is one of the representative compounds of histone deacetylase inhibitors (HDACis) and is used widely for the clinical treatment of epilepsy and other convulsive diseases.

scholarly journals Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation

2015 ◽  
Vol 116 (3) ◽  
pp. 374-380 ◽  
Author(s):  
Andrea O. Fontana ◽  
Marc A. Augsburger ◽  
Nicole Grosse ◽  
Matthias Guckenberger ◽  
Anthony J. Lomax ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Repair Pathway ◽  
Photon Irradiation ◽  
Pathway Choice

scholarly journals DNA Repair Defects in Sarcomas

2020 ◽  
Author(s):  
Niknam Riyahi ◽  
M. Reza Saadatzadeh ◽  
Khadijeh Bijangi-Vishehsaraei ◽  
Farinaz Barghi ◽  
Pankita H. Pandya ◽  
...  
Keyword(s):  
Overall Survival ◽  
Drug Resistance ◽  
Dna Repair ◽  
Cancer Cells ◽  
Large Degree ◽  
Repair System ◽  
Repair Pathway ◽  
Cancer Aggressiveness ◽  
Repair Activity ◽  
Degree Of Heterogeneity

DNA repair pathway is considered to be one of the most important mechanisms that protect cells from intrinsic and extrinsic stresses. It has been established that DNA repair activity has a crucial role in the way that cancer cells respond to treatment. Sarcomas are a group of tumors with mesenchymal origin in which their association with DNA repair aberrations has been reported in numerous studies. Special attention has been focused on exploiting these alterations to improve the patient’s overall survival and overcome drug resistance in cancer. While there is a large degree of heterogeneity among different types of sarcomas, DNA repair alteration is found to be a common defect in the majority of patients. In this chapter, we will introduce and review some of the most important dysregulated components involved in the DNA repair system, and discuss their association with tumorigenesis, cancer aggressiveness, drug resistance, and overall prognosis in the patients with sarcomas.

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6074-6082 ◽  
Author(s):  
Montaser Shaheen ◽  
Christopher Allen ◽  
Jac A. Nickoloff ◽  
Robert Hromas
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Double Strand Breaks ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Repair Pathways ◽  
Cancer Multiple

Abstract Because cancer at its origin must acquire permanent genomic mutations, it is by definition a disease of DNA repair. Yet for cancer cells to replicate their DNA and divide, which is the fundamental phenotype of cancer, multiple DNA repair pathways are required. This produces a paradox for the cancer cell, where its origin is at the same time its weakness. To overcome this difficulty, a cancer cell often becomes addicted to DNA repair pathways other than the one that led to its initial mutability. The best example of this is in breast or ovarian cancers with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks. Because replicating DNA requires repair of DNA double-strand breaks, these cancers have become reliant on another DNA repair component, PARP1, for replication fork progression. The inhibition of PARP1 in these cells results in catastrophic double-strand breaks during replication, and ultimately cell death. The exploitation of the addiction of cancer cells to a DNA repair pathway is based on synthetic lethality and has wide applicability to the treatment of many types of malignancies, including those of hematologic origin. There is a large number of novel compounds in clinical trials that use this mechanism for their antineoplastic activity, making synthetic lethality one of the most important new concepts in recent drug development.

scholarly journals Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells

2020 ◽  
pp. 201920165
Author(s):  
Liton Kumar Saha ◽  
Mitsuo Wakasugi ◽  
Salma Akter ◽  
Rajendra Prasad ◽  
Samuel H. Wilson ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Topoisomerase I ◽  
Excision Repair ◽  
Skin Fibroblasts ◽  
Patch Repair ◽  
Repair Pathway ◽  
Repair Synthesis ◽  
Cellular Tolerance ◽  
Uv Lesions

Nucleotide excision repair (NER) removes helix-destabilizing adducts including ultraviolet (UV) lesions, cyclobutane pyrimidine dimers (CPDs), and pyrimidine (6–4) pyrimidone photoproducts (6–4PPs). In comparison with CPDs, 6–4PPs have greater cytotoxicity and more strongly destabilizing properties of the DNA helix. It is generally believed that NER is the only DNA repair pathway that removes the UV lesions as evidenced by the previous data since no repair of UV lesions was detected in NER-deficient skin fibroblasts. Topoisomerase I (TOP1) constantly creates transient single-strand breaks (SSBs) releasing the torsional stress in genomic duplex DNA. Stalled TOP1-SSB complexes can form near DNA lesions including abasic sites and ribonucleotides embedded in chromosomal DNA. Here we show that base excision repair (BER) increases cellular tolerance to UV independently of NER in cancer cells. UV lesions irreversibly trap stable TOP1-SSB complexes near the UV damage in NER-deficient cells, and the resulting SSBs activate BER. Biochemical experiments show that 6–4PPs efficiently induce stable TOP1-SSB complexes, and the long-patch repair synthesis of BER removes 6–4PPs downstream of the SSB. Furthermore, NER-deficient cancer cell lines remove 6–4PPs within 24 h, but not CPDs, and the removal correlates with TOP1 expression. NER-deficient skin fibroblasts weakly express TOP1 and show no detectable repair of 6–4PPs. Remarkably, the ectopic expression of TOP1 in these fibroblasts led them to completely repair 6–4PPs within 24 h. In conclusion, we reveal a DNA repair pathway initiated by TOP1, which significantly contributes to cellular tolerance to UV-induced lesions particularly in malignant cancer cells overexpressing TOP1.

Valproic acid sensitizes breast cancer cells to hydroxyurea through inhibiting RPA2 hyperphosphorylation-mediated DNA repair pathway

DNA Repair ◽  
2017 ◽  
Vol 58 ◽  
pp. 1-12 ◽  
Author(s):  
Youjia Tian ◽  
Guochao Liu ◽  
Hui Wang ◽  
Zhujun Tian ◽  
Zuchao Cai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Valproic Acid ◽  
Dna Repair ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Repair Pathway

scholarly journals Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2647
Author(s):  
Suzanne Bakewell ◽  
Isabel Conde ◽  
Yassi Fallah ◽  
Mathew McCoy ◽  
Lu Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Parp Inhibitor ◽  
Maximum Tolerated Dose ◽  
Repair Pathway

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 μM, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER−) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER− breast cancer.

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