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Targeting the DNA damage response in cancer. | LitMetric

Targeting the DNA damage response in cancer.

MedComm (2020)

Laboratory of Preclinical Gynecological Oncology Department of Experimental Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy.

Published: November 2024

AI Article Synopsis

  • The DNA damage response (DDR) pathway is a critical cellular network that detects and repairs DNA damage, ensuring proper cell cycle progression and reducing genetic issues in daughter cells.
  • Mutations in key DDR proteins are commonly found in human cancers, leading to genomic instability and offering potential targets for cancer therapies.
  • Recent research has focused on developing and testing DDR inhibitors, which can delay DNA repair, enhance sensitivity to treatments like chemotherapy and radiotherapy, and exploit synthetic lethality to selectively target cancer cells with DDR defects.

Article Abstract

DNA damage response (DDR) pathway is the coordinated cellular network dealing with the identification, signaling, and repair of DNA damage. It tightly regulates cell cycle progression and promotes DNA repair to minimize DNA damage to daughter cells. Key proteins involved in DDR are frequently mutated/inactivated in human cancers and promote genomic instability, a recognized hallmark of cancer. Besides being an intrinsic property of tumors, DDR also represents a unique therapeutic opportunity. Indeed, inhibition of DDR is expected to delay repair, causing persistent unrepaired breaks, to interfere with cell cycle progression, and to sensitize cancer cells to several DNA-damaging agents, such as radiotherapy and chemotherapy. In addition, DDR defects in cancer cells have been shown to render these cells more dependent on the remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over the past two decades has led to the synthesis and testing of hundreds of small inhibitors against key DDR proteins, some of which have shown antitumor activity in human cancers. In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state-of-art of ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527828PMC
http://dx.doi.org/10.1002/mco2.788DOI Listing

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