The Effect of Replication Protein A Inhibition and Post-Translational Modification on ATR Kinase Signaling DOI Creative Commons
Matthew R. Jordan, Greg G. Oakley, Lindsey D. Mayo

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 26, 2024

The ATR kinase responds to elevated levels of single-stranded DNA (ssDNA) activate the G2/M checkpoint, regulate origin utilization, preserve fork stability, and allow repair towards ensuring genome integrity. intrinsic replication stress in cancer cells makes this pathway an attractive therapeutic target. ssDNA that drives signaling is sensed by ssDNA-binding protein A (RPA), which acts as a platform for ATRIP recruitment subsequent activation TopBP1. We have developed chemical RPA inhibitors (RPAi) block RPA-ssDNA interactions, termed RPA-DBi, protein-protein RPA-PPIi; both activities are required activation. Here, we employ biochemically reconstituted demonstrate RPA-DBi RPA-PPIi abrogate ATR-dependent phosphorylation downstream target proteins. post-translational modifications (PTMs) impact but do not alter sensitivity RPAi. Specifically, RPA32 TopBP1 stimulate, while RPA70 acetylation has no effect on Collectively, work reveals RPAi mechanism action inhibit can be regulated PTMs offers insight into anti-cancer activity targeted therapeutics.

Language: Английский

Emerging strategies for cancer therapy by ATR inhibitors DOI Creative Commons

Kimiyoshi Yano,

Bunsyo Shiotani

Cancer Science, Journal Year: 2023, Volume and Issue: 114(7), P. 2709 - 2721

Published: May 15, 2023

DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, fork stabilization to secure fidelity of replication. However, also alleviates RS support survival by driving tolerance, thereby contributing therapeutic resistance. Cancer harboring genetic mutations other changes that disrupt normal increase risk damage levels conferring addiction activity for sustainable susceptibility approaches using inhibitors (ATRis). Therefore, clinical trials are currently being conducted evaluate efficacy ATRis as monotherapies or combination with drugs biomarkers. In this review, we discuss recent advances elucidation functions response its relevance when utilizing ATRis.

Language: Английский

Citations

29
WEE1 Inhibition by AZD1775 Augments Colorectal Cancer Cells Susceptibility to VE-822-induced DNA Damage and Apoptosis DOI
Ainaz Mihanfar,

Faezeh Asghari,

Maryam Majidinia

et al.

Drug Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract WEE1 is a key tyrosine kinase involved in the cell cycle regulation with potent anticancer effects various cancer types including colorectal cancer. Recent studies have focused on potential of combinational inhibition Ataxia Telangiectasia and Rad-3-related protein (ATR) increasing apoptosis cells. Therefore, this study investigates inhibiting WEE1, by employing AZD1775, cellsʼ susceptibility to VE-822-induced DNA damage apoptosis. SW-480 HT-29 cells were treated AZD1775 VE-822, alone combination. MTT assay was used assess proliferation viability. The mRNA levels ATR, checkpoint 1 (CHK1), ribonucleotide reductase (RR) catalytic subunit M1 (RRM1) RRM2 measured qRT-PCR. Cellular γ-(H2A histone family member X) H2AX Western blot. Analyses conducted using ELISA 8-Oxo-2ʼ-deoxyguanosine (8-oxo-dG) levels. Lactate dehydrogenase (LDH) death assays low rate when VE-822 AZD1775. IC50 value for 1.3 μM 1.6 SW480 HT-29, respectively. Also, 140 nM 185 nM. expression CHK1, RRM1, significantly downregulated both lines combination (P<0.05). markers, γ-H2AX 8-oxo-dG upregulated these Simultaneous treatment AZD177 increased capacity lines. via potentiated ATR inhibitor, combating targeting damage.

Language: Английский

Citations

1
Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer DOI Creative Commons
Yijun Xie, Di Xiao, Duo Li

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Aug. 2, 2024

Genomic instability stands out as a pivotal hallmark of cancer, and PARP inhibitors (PARPi) emerging groundbreaking class targeted therapy drugs meticulously crafted to inhibit the repair DNA single-strand breaks(SSB) in tumor cells. Currently, PARPi have been approved for treatment ovarian pancreatic breast prostate cancer characterized by homologous recombination(HR) deficiencies due mutations BRCA1/2 or other associated genes acquiring designation breakthrough therapy. Nonetheless, exhibit limited efficacy majority HR-proficient

Language: Английский

Citations

6
DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines DOI Open Access
Tassanee Lerksuthirat, Sunisa Prasopporn, Rakkreat Wikiniyadhanee

et al.

Oncology Letters, Journal Year: 2025, Volume and Issue: 29(3)

Published: Jan. 7, 2025

Cholangiocarcinoma (CCA) is a biliary tract carcinoma that challenging to treat due its heterogeneity and limited treatment options. Genetic alterations in DNA damage response (DDR) pathways homologous recombination (HR) defects are common CCA. This has prompted interest the use of ataxia telangiectasia Rad3-related protein (ATR) poly(ADP-ribose) polymerase (PARP) inhibitors The present study investigated impact an ATR inhibitor various PARP inhibitors, individually combination, on CCA cell lines with different DDR mutation profiles. gene these were analyzed, responses cells olaparib, veliparib talazoparib and/or AZD6738 evaluated. Assessments focused cellular viability, clonogenic survival combination index, alongside changes assessed via formation micronuclei γ-H2A histone family member X foci. results revealed more mutations exhibited greater sensitivity single treatments. Talazoparib was found be most potent lines. demonstrated varying synergistic effects depending genetic background cells, efficacy less sensitive drug Mechanistically, this promoted accumulation damage, including double-strand breaks. Overall, underscores importance HR It reveals association between extent CCA, both as agents combination. These findings highlight number mutated genes influences variability response.

Language: Английский

Citations

0
Design, Synthesis and Evaluation of Quinazoline-Chalcone Hybrids as Inducers of Cell-Cycle Arrest and Apoptosis in Breast Cancer via DNA Damage and CDK2/ATR Inhibition DOI Creative Commons
Giulia Rodrigues Stringhetta, Eduardo Bustos Mass, Izabela Natália Faria Gomes

et al.

European Journal of Medicinal Chemistry Reports, Journal Year: 2025, Volume and Issue: unknown, P. 100250 - 100250

Published: Feb. 1, 2025

Language: Английский

Citations

0
The Development of ATM Inhibitors in Cancer Therapy DOI Creative Commons

Elizabeth A. Ampolini,

Judit Jiménez-Sáinz, David T. Long

et al.

Targeted Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The ataxia-telangiectasia mutated (ATM) protein kinase plays a critical role in activating the cellular response to DNA double-strand breaks and promoting homology-directed repair. ATM is frequently cancer, contributing an accumulation of damage that drives genomic instability. To exploit cancer cells' inherent vulnerability damage, various small molecule inhibitors have been developed target ATM. shown great versatility preclinical studies increasing use clinic. Here, we review development their therapy. We describe limitations advances led increases both number diversity active clinical trials targeting also discuss ATM's personalized medicine current challenges more widespread

Language: Английский

Citations

0
Hypoxia‐Responsive Prodrug of ATR Inhibitor, AZD6738, Selectively Eradicates Treatment‐Resistant Cancer Cells DOI Creative Commons
Francis M. Barnieh, Goreti Ribeiro Morais, Paul M. Loadman

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 8, 2024

Targeted therapy remains the future of anti-cancer drug development, owing to lack specificity current treatments which lead damage in healthy normal tissues. ATR inhibitors have recent times demonstrated promising clinical potential, and are currently being evaluated clinic. However, despite considerable optimism for success these inhibitors, reports associated tissues toxicities remain a concern can compromise their utility. Here, ICT10336 is reported, newly developed hypoxia-responsive prodrug inhibitor, AZD6738, hypoxia-activated specifically releases AZD6738 only hypoxic conditions, vitro. This hypoxia-selective release inhibited activation (T1989 S428 phosphorylation) subsequently abrogated HIF1a-mediated adaptation cancers cells, thus selectively inducing cell death 2D 3D cancer models. Importantly, tissues, be metabolically stable less toxic cells than its active parent agent, AZD6738. In addition, exhibited superior efficient multicellular penetration ability tumor models, eradicated at core compared summary, preclinical data demonstrate new strategy tumor-targeted delivery with significant potential enhancing therapeutic index.

Language: Английский

Citations

3
PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells DOI Creative Commons

Kimiyoshi Yano,

Megumi Kato, Satoshi Endo

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 28, 2025

Abstract DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability cancer cells to ataxia telangiectasia Rad3-related kinase inhibitors (ATRis). Here, we screened for damage response that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient identified potent synergy between ATRi poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells. PARP inhibition triggers chromatin changes, namely elevated histone H3 at lysine 9 di-methylation (H3K9me2), hallmark facultative heterochromatin, increasing dependence on ATR activity fork progression cell survival. Interestingly, SMARCA4 deficient cells, intrinsically vulnerable stress, exhibited exacerbated upon combined PARPi treatment Mre11- Mus81-mediated manner. In vivo, with intermittent continuous showed greater tumor growth than alone lung adenocarcinoma xenograft models. These findings demonstrate PARPi-induced heterochromatin amplifies susceptibility, providing potential rationale therapeutic strategies targeting tumors.

Language: Английский

Citations

0
Kinase Inhibitor-Induced Cell-Type Specific Vacuole Formation in the Absence of Canonical ATG5-Dependent Autophagy Initiation Pathway DOI

Susan Jose,

Himanshi Sharma,

Janki Insan

et al.

Molecular and Cellular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: Feb. 2, 2025

Pyridinyl-imidazole class p38 MAPKα/β (MAPK14/MAPK11) inhibitors including SB202190 have been shown to induce cell-type specific defective autophagy resulting in micron-scale vacuole formation, cell death, and tumor suppression. We had earlier that this is an off-target effect of SB202190. Here we provide evidence formation independent ATG5-mediated canonical autophagosome initiation. While interferes with autophagic flux many lines parallel vacuolation, autophagy-deficient DU-145 cells CRISPR/Cas9 gene-edited ATG5-knockout A549 also undergo vacuolation upon treatment. Late-endosomal GTPase RAB7 colocalizes these compartments GTP-binding essential for SB202190-induced vacuolation. A screen modulators revealed molecules multi-kinase inhibitor sorafenib as co-treatment enhanced cytotoxicity Moreover, VE-821, ATR was found phenocopy the response To identify factors determining specificity induced by SB-compounds compared transcriptomics data from vacuole-forming non-vacuole-forming cancer identified a gene expression signature may define sensitivity small-molecules. Further analyses using small molecule tools discovered here, could reveal novel mechanisms regulating interesting anti-cancer phenotype.

Language: Английский

Citations

0
Locking the gates of immortality: targeting alternative lengthening of telomeres (ALT) pathways DOI
Apurwa Mishra, Trupti Patel

Medical Oncology, Journal Year: 2025, Volume and Issue: 42(3)

Published: Feb. 18, 2025

Language: Английский

Citations

0