Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

Tomasini, Paula Pellenz; Guecheva, Temenouga Nikolova; Leguisamo, Natalia Motta; Péricart, Sarah; Brunac, Anne-Cécile; Hoffmann, Jean-Sébastien; Saffi, Jenifer

doi:10.3390/cancers13133130

Cited by 15 publications

(12 citation statements)

References 273 publications

(349 reference statements)

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“…The collision of unrepaired single-strand lesions with the replication fork along with replication stalling due to replication firing (often oncogene driven) with inadequate nucleotide supply causes RS [ 2 ]. RS is also resolved by HRR and is an important activator of ATR, CHK1 and WEE1 signalling to cell cycle arrest [ 21 ].…”

Section: Double Strand Damagementioning

confidence: 99%

Targeting the DNA damage response for cancer therapy

Curtin

2023

Biochemical Society Transactions

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The DNA damage response (DDR) is an elegant system, coordinating DNA repair with cell cycle checkpoints, that evolved to protect living organisms from the otherwise fatal levels of DNA damage inflicted by endogenous and environmental sources. Since many agents used to treat cancer; radiotherapy and cytotoxic chemotherapy, work by damaging DNA the DDR represents a mechanism of resistance. The original rational for the development of drugs to inhibit the DDR was to overcome this mechanism of resistance but clinical studies using this approach have not led to improvements in the therapeutic index. A more exciting approach is to exploit cancer-specific defects in the DDR, that represent vulnerabilities in the tumour and an opportunity to selectively target the tumour. PARP inhibitors (PARPi) selectively kill homologous recombination repair defective (HRD, e.g. through BRCA mutation) cells. This approach has proven successful clinically and there are now six PARPi approved for cancer therapy. Drugs targeting other aspects of the DDR are under pre-clinical and clinical evaluation as monotherapy agents and in combination studies. For this promising approach to cancer therapy to be fully realised reliable biomarkers are needed to identify tumours with the exploitable defect for monotherapy applications. The possibility that some combinations may result in toxicity to normal tissues also needs to be considered. A brief overview of the DDR, the development of inhibitors targeting the DDR and the current clinical status of such drugs is described here.

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Section: Double Strand Damagementioning

confidence: 99%

Targeting the DNA damage response for cancer therapy

Curtin

2023

Biochemical Society Transactions

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“…DNA damage repair mechanisms include base excision repair (BER), mismatch repair (MMR), and homologous recombination (HR). These mechanisms identify and correct DNA damage caused by multiple factors such as reactive oxygen species (ROS), radiation, and chemicals ( 31 , 32 ). DNA damage repair, not only removes the damaged cells but also assists in drug resistance ( Figure 2 ) ( 33 , 34 ).…”

Section: Tcm Reverses the Chemoresistance Of Crc And Inhibits Tumor G...mentioning

confidence: 99%

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

Lin

Yang

et al. 2023

Front. Oncol.

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In recent years, the incidences and mortalities from colorectal cancer (CRC) have been increasing; therefore, there is an urgent need to discover newer drugs that enhance drug sensitivity and reverse drug tolerance in CRC treatment. With this view, the current study focuses on understanding the mechanism of CRC chemoresistance to the drug as well as exploring the potential of different traditional Chinese medicine (TCM) in restoring the sensitivity of CRC to chemotherapeutic drugs. Moreover, the mechanism involved in restoring sensitivity, such as by acting on the target of traditional chemical drugs, assisting drug activation, increasing intracellular accumulation of anticancer drugs, improving tumor microenvironment, relieving immunosuppression, and erasing reversible modification like methylation, have been thoroughly discussed. Furthermore, the effect of TCM along with anticancer drugs in reducing toxicity, increasing efficiency, mediating new ways of cell death, and effectively blocking the drug resistance mechanism has been studied. We aimed to explore the potential of TCM as a sensitizer of anti-CRC drugs for the development of a new natural, less-toxic, and highly effective sensitizer to CRC chemoresistance.

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“…Second, PARP inhibitors inhibit the repair of NHEJ, leading to cell apoptosis or necrosis after DNA damage occurs (Gupta et al, 2018). Third, some new studies have shown that PARP inhibitors reduce the repair efficiency of MMEJ, an auxiliary DNA repair mechanism (Tomasini et al, 2021). This speeds up the process of apoptosis, or death, in cancer cells that do not initiate the required DNA repair.…”

Section: Dna-damaging Agents In Gastric Cancermentioning

confidence: 99%

DNA Damage Repair and Current Therapeutic Approaches in Gastric Cancer: A Comprehensive Review

Wang

Xie

2022

Front. Genet.

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DNA in cells is frequently damaged by endogenous and exogenous agents. However, comprehensive mechanisms to combat and repair DNA damage have evolved to ensure genomic stability and integrity. Improper DNA damage repair may result in various diseases, including some types of tumors and autoimmune diseases. Therefore, DNA damage repair mechanisms have been proposed as novel antitumor drug targets. To date, numerous drugs targeting DNA damage mechanisms have been developed. For example, PARP inhibitors that elicit synthetic lethality are widely used in individualized cancer therapies. In this review, we describe the latent DNA damage repair mechanisms in gastric cancer, the types of DNA damage that can contribute to the development of gastric cancer, and new therapeutic approaches for gastric cancer that target DNA damage repair pathways.

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Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

Cited by 15 publications

References 273 publications

Targeting the DNA damage response for cancer therapy

Targeting the DNA damage response for cancer therapy

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

DNA Damage Repair and Current Therapeutic Approaches in Gastric Cancer: A Comprehensive Review

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