Review
Biochemistry & Molecular Biology
Wonyoung Choi, Eun Sook Lee
Summary: The DNA damage response (DDR) pathway plays a critical role in maintaining genome stability and defects in this pathway are associated with cancer. Exploiting vulnerabilities in this pathway has led to successful anticancer therapies, such as PARP inhibitors. This review discusses key elements of the DDR pathway and the development of pharmacologic inhibitors. It also highlights the importance of biomarker studies and combination strategies in optimizing clinical benefits.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Oncology
Lindsey Carlsen, Wafik S. El-Deiry
Summary: DNA damage response inhibitors are effective anti-cancer agents that sensitize tumor cells to radiotherapy and chemotherapy while also stimulating immune responses. However, the contribution of different inhibitors and genetic aberrations in cancers to immune mechanisms is not well-characterized, limiting the optimization of treatment regimens.
FRONTIERS IN ONCOLOGY
(2022)
Article
Food Science & Technology
Zhuangzhuang Jiang, Yang Zhao, Yanqing Liu, Li Tao
Summary: The combination of gemcitabine and pristimerin shows effective synergy in pancreatic cancer cells, with pristimerin acting as a natural inhibitor of the replication stress response (RSR) and enhancing the apoptotic potential of PC cells.
FOOD AND CHEMICAL TOXICOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Thomas Fischer, Oliver Hartmann, Michaela Reissland, Cristian Prieto-Garcia, Kevin Klann, Nikolett Pahor, Christina Schuelein-Voelk, Apoorva Baluapuri, Bulent Polat, Arya Abazari, Elena Gerhard-Hartmann, Hans-Georg Kopp, Frank Essmann, Mathias Rosenfeldt, Christian Muench, Michael Flentje, Markus E. Diefenbacher
Summary: Loss of PTEN leads to increased resistance of lung cancer cells to radiation therapy, but with significant dependence on ATM kinase. Inhibition of ATM can restore sensitivity to radiation therapy and synergize with it.
CELL AND BIOSCIENCE
(2022)
Article
Oncology
Amr Ghaleb, Lucia Roa, Natalia Marchenko
Summary: The biological consequences of low-dose radiation (LDR) in breast cancer are unclear, while high-dose radiation (HDR) promotes DNA repair and cell cycle arrest. Mutant p53 promotes mammary tumorigenesis following LDR, but has negligible effects on tumors carrying the wild-type p53 allele.
Article
Pharmacology & Pharmacy
Haiying Zhu, Zijian Rao, Sichen Yuan, Jieqiong You, Chenggang Hong, Qiaojun He, Bo Yang, Chengyong Du, Ji Cao
Summary: The combination treatment of carboplatin with the Chk1 inhibitor AZD7762 synergistically inhibits TNBC cell growth by inducing mitotic catastrophes, leading to multinucleation, polyploidization, and apoptosis in tumor cells. This suggests that Chk1 could be a therapeutic target for combination therapy in TNBC, and mitotic catastrophe induction could be an alternative strategy for TNBC therapy.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Andrey Anisenko, Anastasiia Nefedova, Yulia Agapkina, Marina Gottikh
Summary: The DNA copy of HIV-1 RNA genome integration into the host genome requires repair of single-stranded gaps in cellular DNA, involving the DNA damage response (DDR) kinases ATM, ATR, and DNA-PKcs. Inhibition of DNA-PKcs and ATM, but not ATR, reduces the efficiency of post-integrational DNA repair (PIR), suggesting that the activation of both kinases is crucial for PIR, and their activation depends on the formation of a complex between integrase and Ku70. The elucidation of virus-DDR interactions is essential for understanding host cell modulation and developing strategies against viral infections.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Watanya Trakarnphornsombat, Hiroshi Kimura
Summary: DNA double-strand breaks (DSBs) can cause genetic mutation and histone H2AX is phosphorylated by kinases such as ATM, ATR, and DNA-PK upon DSB induction. The accumulation kinetics of ?-H2AX were similar in ATM-proficient and-deficient cells, but delayed in the presence of a DNA-PK inhibitor. Ku80 (XRCC5) diffuses freely in the nucleus, while ATM repeatedly binds to and dissociates from chromatin. ATM accumulation at damage sites is regulated by the histone acetyltransferase MOF, but does not necessarily reflect in the ?-H2AX level, suggesting distinct actions of ATM and DNA-PK in immediate ?-H2AX accumulation.
JOURNAL OF CELL SCIENCE
(2023)
Review
Cell Biology
Luisa Maresca, Barbara Stecca, Laura Carrassa
Summary: Targeted therapies and immunotherapies have shown clinical benefits in melanoma patients, but resistance and relapse are common. This review discusses the potential of exploiting DNA damage response (DDR) as a therapeutic approach in melanoma. The use of DDR inhibitors, both as single agents and in combination with other therapies, shows promise in preclinical studies and ongoing clinical trials.
Article
Multidisciplinary Sciences
Makoto Isono, Kazuki Okubo, Takako Asano, Akinori Sato
Summary: The combination of gemcitabine and the ATR inhibitor AZD6738 showed efficacy in inhibiting bladder cancer cell viability, colony formation, and promoting apoptosis. Mechanistically, AZD6738 interfered with CHK1 and hindered the repair of DNA damage induced by gemcitabine.
Article
Cell Biology
Swati Priya, Ekjot Kaur, Swati Kulshrestha, Awadhesh Pandit, Isabelle Gross, Nitin Kumar, Himanshi Agarwal, Aamir Khan, Radhey Shyam, Prakash Bhagat, Jyothi S. Prabhu, Perumal Nagarajan, S. V. S. Deo, Avinash Bajaj, Jean-Noel Freund, Arnab Mukhopadhyay, Sagar Sengupta
Summary: A DNA damage responsive miR signature called DNA damage sensitive miRs (DDSMs) was identified in colon adenocarcinoma patient tissues, which were upregulated by the intestine-specific transcription factor CDX2 and repressed by HDAC1/2-containing complexes. These miRs downregulated key targets in the DNA damage response pathway and were associated with decreased survival probability in colon cancer patients, showing potential as a prognostic biomarker.
JOURNAL OF CELL SCIENCE
(2021)
Review
Oncology
Marwan Kwok, Angelo Agathanggelou, Nicholas Davies, Tatjana Stankovic
Summary: The p53 pathway is crucial in maintaining genome integrity and its loss of function is associated with the development and therapeutic resistance in chronic lymphocytic leukemia. Therapeutic strategies targeting p53 pathway defects include activating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations.
Article
Genetics & Heredity
Eva-Maria Faulhaber, Tina Jost, Julia Symank, Julian Scheper, Felix Buerkel, Rainer Fietkau, Markus Hecht, Luitpold Distel
Summary: The combination of kinase inhibitors targeting components of the DNA damage repair pathway and ionizing radiation therapy could potentially improve tumor control, increase cell death in malignant cells, have limited impact on healthy cells, reduce metastasis formation, and enhance treatment outcomes for HPV-negative tumors.
Article
Multidisciplinary Sciences
Makoto Isono, Kazuki Okubo, Takako Asano, Akinori Sato
Summary: Combining MK-8776 with gemcitabine inhibits viability and colony formation of bladder cancer cells, induces apoptosis, and suppresses tumor growth in vivo. The combination treatment elevates gamma H2A.X and suppresses Rad51 expression, suggesting CHK1 inhibition combined with gemcitabine as a potential therapeutic strategy for bladder cancer.
SCIENTIFIC REPORTS
(2021)
Review
Oncology
Congqi Shi, Kaiyu Qin, Anqi Lin, Aimin Jiang, Quan Cheng, Zaoqu Liu, Jian Zhang, Peng Luo
Summary: This study summarizes currently identified and promising biomarkers for predicting the response of oncology patients to immune checkpoint inhibitors, and explores the mechanism of combination therapy with immune checkpoint inhibitors and DNA damage repair inhibitors.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)