Familial Pancreatic Cancer Research: Bridging Gaps in Basic Research and Clinical Application DOI Open Access

Suyakarn Archasappawat,

Fatimah Al-Musawi,

Peiyi Liu

et al.

Published: Aug. 5, 2024

Familial pancreatic cancer (FPC) represents a significant yet underexplored area in research. Basic research efforts are notably limited, and when present, they predominantly centered on BRCA1 BRCA2 mutations due to the scarcity of other genetic variants associated with FPC, leading limited understanding broader landscape FPC. This review examines current state FPC research, focusing molecular mechanisms driving ductal adenocarcinoma (PDAC) progression. It highlights role homologous recombination (HR) its therapeutic exploitation via synthetic lethality PARP inhibitors BRCA1/2-deficient tumors. The discusses various pre-clinical models including conventional two-dimensional (2D) cell lines, patient-derived organoids (PDOs), xenografts (PDXs), genetically engineered mouse (GEMMs) as well new advancements

Language: Английский

When DNA-damage responses meet innate and adaptive immunity DOI Creative Commons
Jie Tong, Jiangwei Song,

Wuchao Zhang

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: April 17, 2024

Abstract When cells proliferate, stress on DNA replication or exposure to endogenous external insults frequently results in damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms prevent Depending the type of broken DNA, various pathways, Base-Excision Repair (BER), Nucleotide Excision (NER), Mismatch (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair can be activated separately combination To preserve homeostasis, innate adaptive immune responses effective defenses against mutation invasion pathogens. It is interesting note that new research keeps showing how closely DDR components system related. immunological response linked effectors such as cyclic GMP-AMP synthase (cGAS)–Stimulator Interferon Genes (STING) pathway. These act sensors damage-caused response. Furthermore, themselves function trigger generation inflammatory cytokines a cascade even programmed cell death. Defective known disrupt genomic stability compromise responses, aggravating imbalance leading serious diseases cancer autoimmune disorders. This study examines most recent developments interaction between elements responses. The network’s modulators’ dual roles may offer perspectives treating infectious disorders damage, including cancer, development target immunotherapy.

Language: Английский

Citations

20
Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage DOI Creative Commons
Radosław Szmyd, Sienna Casolin,

Lucy French

et al.

Nature Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Language: Английский

Citations

2
PARP Inhibitors in Breast and Ovarian Cancer DOI Open Access
Samuel Sherng Young Wang,

Yeo Ee Jie,

Sim Wey Cheng

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(8), P. 2357 - 2357

Published: April 18, 2023

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples clinical translation targeted therapies in medical oncology, and this has been demonstrated by their effective management BRCA1/BRCA2 mutant cancers, notably breast ovarian cancers. PARP target DNA repair pathways that BRCA1/2-mutant tumours dependent upon. Inhibition key components these leads to damage triggering subsequent critical levels genomic instability, mitotic catastrophe cell death. This ultimately results a synthetic lethal relationship between BRCA1/2 PARP, which underpins effectiveness inhibitors. Despite early dramatic response seen with inhibitors, patients receiving them often develop treatment resistance. To date, data from both preclinical studies have highlighted multiple resistance mechanisms only understanding we able overcome challenges. The focus review is summarise underlying underpinning aid clinicians scientists better clinically applicable assays select who would derive greatest benefit as well new novel/combination strategies With inhibitor mechanisms, not be identify subset unlikely therapy but also sequence our paradigm avoid mechanisms.

Language: Английский

Citations

26
PARPi, BRCA, and gaps: controversies and future research DOI Creative Commons
Diego Dibitetto, Carmen A. Widmer, Sven Rottenberg

et al.

Trends in cancer, Journal Year: 2024, Volume and Issue: 10(9), P. 857 - 869

Published: July 14, 2024

In recent years, various poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been approved for the treatment of several cancers to target vulnerability homologous recombination (HR) deficiency (e.g., due BRCA1/2 dysfunction). this review we analyze ongoing debates and breakthroughs in use PARPis BRCA1/2-deficient cancers, juxtaposing 'double-strand break (DSB)' 'single-stranded DNA (ssDNA) gap' models synthetic lethality induced by PARPis. We spotlight complexity interaction, highlighting emerging research on role theta (POLθ) ssDNA gaps shaping therapy responses. scrutinize clinical ramifications these findings, especially concerning PARPi efficacy resistance mechanisms, underscoring heterogeneity BRCA-mutated tumors urgent need advanced bridge gap between laboratory patient outcomes.

Language: Английский

Citations

10
Freedom to err: The expanding cellular functions of translesion DNA polymerases DOI Creative Commons
Inés Paniagua, Jacqueline J.L. Jacobs

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(20), P. 3608 - 3621

Published: Aug. 24, 2023

Language: Английский

Citations

20
Novobiocin blocks nucleic acid binding to Polθ and inhibits stimulation of its ATPase activity DOI Creative Commons
Aleem Syed, František Filandr, Jeffrey Patterson-Fortin

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(18), P. 9920 - 9937

Published: Aug. 25, 2023

Abstract Polymerase theta (Polθ) acts in DNA replication and repair, its inhibition is synthetic lethal BRCA1 BRCA2-deficient tumor cells. Novobiocin (NVB) a first-in-class inhibitor of the Polθ ATPase activity, it currently being tested clinical trials as an anti-cancer drug. Here, we investigated molecular mechanism NVB-mediated inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational cellular assays, found NVB non-competitive ATP hydrolysis. sugar group deletion resulted decreased potency reduced HX-MS interactions, supporting specific binding orientation. Collective results revealed that binds to allosteric site block binding, both vitro Comparisons The Cancer Genome Atlas (TCGA) tumors matched controls implied POLQ upregulation stems from role stress responses increased cell proliferation: this can now be fifteen types by blocking ssDNA-stimulation required for function at forks damage sites. Structural functional insights provided study suggest path developing derivatives with improved targeting ssDNA entropically constrained small molecules.

Language: Английский

Citations

18
The power and the promise of synthetic lethality for clinical application in cancer treatment DOI Open Access
Qianwen Liu, Zhiwen Yang,

Qing-Hai Tang

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 172, P. 116288 - 116288

Published: Feb. 20, 2024

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while any individual gene does not lead to death. In recent years, synthetic has emerged as significant topic field targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes clinical trials. Nevertheless, presence tumor heterogeneity and intricate DNA repair mechanisms pose challenges effective implementation lethality. This review aims explore concepts, development, ethical quandaries surrounding Additionally, it will provide an in-depth analysis application underlying mechanism

Language: Английский

Citations

6
The crosstalk between DNA-damage responses and innate immunity DOI Creative Commons

Mei He,

Hua Jiang,

Shun Li

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 140, P. 112768 - 112768

Published: July 31, 2024

DNA damage is typically caused during cell growth by replication stress or exposure to endogenous external toxins. The accumulation of damaged causes genomic instability, which the root cause many serious disorders. Multiple cellular organisms utilize sophisticated signaling pathways against damage, collectively known as response (DDR) networks. Innate immune responses are activated following abnormalities, including damage. Interestingly, recent studies have indicated that there an intimate relationship between DDR network and innate responses. Diverse kinds cytosolic sensors, such cGAS STING, recognize induce signals related responses, link defective immunity. Moreover, components operate in IFNs and/or a cascade inflammatory cytokines via direct interactions with modulators. Consistently, factors exacerbate imbalance, resulting severe diseases, autoimmune disorders tumorigenesis. Here, latest progress understanding crosstalk reviewed. Notably, dual function modulators may provide novel insights into developing targeted immunotherapies for damage-related even carcinomas.

Language: Английский

Citations

6
Cancer cell-specific cGAS/STING Signaling pathway in the era of advancing cancer cell biology DOI Creative Commons
Vijay Kumar,

Caitlin Bauer,

John H. Stewart

et al.

European Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 102(3), P. 151338 - 151338

Published: July 6, 2023

Pattern-recognition receptors (PRRs) are critical to recognizing endogenous and exogenous threats mount a protective proinflammatory innate immune response. PRRs may be located on the outer cell membrane, cytosol, nucleus. The cGAS/STING signaling pathway is cytosolic PRR system. Notably, cGAS also present in cGAS-mediated recognition of dsDNA its cleavage into cGAMP activates STING. Furthermore, STING activation through downstream triggers different interferon-stimulating genes (ISGs), initiating release type 1 interferons (IFNs) NF-κB-mediated cytokines molecules. Activating generates IFN, which prevent cellular transformation cancer development, growth, metastasis. current article delineates impact cell-specific alteration tumors tumor growth This further discusses approaches specifically target cells inhibit metastasis conjunction with existing anticancer therapies.

Language: Английский

Citations

14
Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets DOI Creative Commons
Yutong Zhao,

C.M. Qin,

Lin Chen

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(6), P. 189183 - 189183

Published: Sept. 19, 2024

Language: Английский

Citations

4