Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.
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http://dx.doi.org/10.1186/s13045-020-00956-5 | DOI Listing |
Drug Discov Today
January 2025
Institute of Immunology, Kiel University (CAU), Kiel, Germany.
Death ligands (DLs), particularly tumor necrosis factor alpha (TNF-α), FAS ligand (FASL), and TNF-related apoptosis-inducing ligand (TRAIL), collectively termed TFT, are pivotal members of the TNF superfamily. While traditionally linked to apoptosis, TFT proteins have emerged as key regulators of various non-apoptotic processes. This review summarizes the non-apoptotic functions of TFT in cancer and explores the intricate crosstalk signaling pathways and their impact on nuclear factor kappa B (NF-κB) signaling, inflammation, and pro-tumorigenic function.
View Article and Find Full Text PDFJ Med Chem
January 2025
Medicinal Chemistry Department, Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Pudong New Area, Shanghai 201203, China.
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of -methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design.
View Article and Find Full Text PDFAdv Exp Med Biol
January 2025
Cancer Research UK Scotland Centre (Edinburgh), Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK.
E-cadherin is a transmembrane protein and central component of adherens junctions (AJs). The extracellular domain of E-cadherin forms homotypic interactions with E-cadherin on adjacent cells, facilitating the formation of cell-cell adhesions, known as AJs, between neighbouring cells. The intracellular domain of E-cadherin interacts with α-, β- and p120-catenins, linking the AJs to the actin cytoskeleton.
View Article and Find Full Text PDFCell Prolif
January 2025
NewStem LTD, Jerusalem, Israel.
Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death, whereas each of them separately does not. Synthetic lethality can be a useful tool in personalised oncology. MLH1 is a cancer-related gene that has a central role in DNA mismatch-repair and TP53 is the most frequently mutated gene in cancer.
View Article and Find Full Text PDFBraz J Microbiol
January 2025
Department of Postgraduate Program in Animal Science, University of Franca (UNIFRAN), Av. Dr. Armando Salles Oliveira, 201, Parque Universitário, Franca, SP, CEP 14.404-600, Brazil.
Failures in endodontic treatments are common due to microbial resistance in the pulp canal. The study evaluated the in vitro activity of polyhexamethylene guanidine hydrochloride (PHMGH) against endodontic strains, as well as in vivo toxicity. Using minimum inhibitory concentration and minimum bactericidal concentration techniques, PHMGH was effective against all microorganisms, even at low concentrations.
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