scholarly journals Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

2021 ◽  
Vol 22 (15) ◽  
pp. 8199
Author(s):  
Robert Csaba Kiss ◽  
Fen Xia ◽  
Scarlett Acklin
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Cisplatin Resistance ◽  
Therapeutic Index ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Damage Response ◽  
Improve Patient ◽  
Treatment Personalization

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.

scholarly journals DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruixue Huang ◽  
Ping-Kun Zhou
Keyword(s):  
Dna Damage ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Dna Damage Repair ◽  
Therapeutic Effects ◽  
Targeted Cancer Therapy ◽  
Baseline Drift ◽  
Damage Repair ◽  
Damage Response

AbstractGenomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells’ DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists’ findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely “environmental gear selection” to describe DNA damage repair pathway evolution, and “DNA damage baseline drift”, which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.

Breaking the DNA damage response to improve cervical cancer treatment

2016 ◽  
Vol 42 ◽  
pp. 30-40 ◽  
Author(s):  
Hylke W. Wieringa ◽  
Ate G.J. van der Zee ◽  
Elisabeth G.E. de Vries ◽  
Marcel A.T.M. van Vugt
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Damage Response

Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment

2019 ◽  
Vol 26 (8) ◽  
pp. 1425-1445 ◽  
Author(s):  
Wioletta Rozpędek ◽  
Dariusz Pytel ◽  
Alicja Nowak-Zduńczyk ◽  
Dawid Lewko ◽  
Radosław Wojtczak ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitors ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Anti Cancer ◽  
Damage Response

Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/ threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death. Interestingly, key components of DDR signaling networks may constitute an attractive target for anti-cancer therapy through two distinct potential approaches: as chemoand radiosensitizers to enhance the effectiveness of currently used genotoxic treatment or as single agents to exploit defects in DDR in cancer cells via synthetic lethal approach. Moreover, the newest data reported that serine/threonine protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is also closely associated with cancer development and progression. Thereby, utilization of small-molecule, serine/threonine kinase inhibitors may provide a novel, groundbreaking, anti-cancer treatment strategy. Currently, a range of potent, highlyselective toward ATM, ATR and PERK inhibitors has been discovered, but after foregoing study, additional investigations are necessary for their future clinical use.

scholarly journals MicroRNAs, DNA Damage Response, and Cancer Treatment

2016 ◽  
Vol 17 (12) ◽  
pp. 2087 ◽  
Author(s):  
Mingyang He ◽  
Weiwei Zhou ◽  
Chuang Li ◽  
Mingxiong Guo
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway

2020 ◽  
Author(s):  
Cristian Prieto-Garcia ◽  
Oliver Hartmann ◽  
Michaela Reissland ◽  
Thomas Fischer ◽  
Carina R. Maier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Cells ◽  
Dna Damage Response ◽  
Fanconi Anemia ◽  
Cisplatin Resistance ◽  
Chemotherapy Resistance ◽  
Fanconi Anemia Pathway ◽  
Platinum Based Chemotherapy ◽  
Damage Response

AbstractSquamous cell carcinomas (SCC) frequently have a limited response to or develop resistance to platinum-based chemotherapy, and have an exceptionally high tumor mutational burden. As a consequence, overall survival is limited and novel therapeutic strategies are urgently required, especially in light of a rising incidences. SCC tumors express ΔNp63, a potent regulator of the Fanconi Anemia (FA) DNA-damage response pathway during chemotherapy, thereby directly contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 affects the FA DNA repair pathway during cisplatin treatment in SCC, thereby influencing therapy outcome. In an ATR-dependent fashion, USP28 is phosphorylated and activated to positively regulate the DNA damage response. Inhibition of USP28 reduces recombinational repair via an ΔNp63-Fanconi Anemia pathway axis, and weakens the ability of tumor cells to accurately repair DNA. Our study presents a novel mechanism by which tumor cells, and in particular ΔNp63 expressing SCC, can be targeted to overcome chemotherapy resistance.SignificanceLimited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ΔNp63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-ΔNp63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.

DNA Damage Response Pathways in Tumor Suppression and Cancer Treatment

2008 ◽  
Vol 33 (4) ◽  
pp. 661-666 ◽  
Author(s):  
Yulong Liang ◽  
Shiaw-Yih Lin ◽  
F. Charles Brunicardi ◽  
John Goss ◽  
Kaiyi Li
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Tumor Suppression ◽  
Damage Response
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