Emerging strategies for cancer therapy by ATR inhibitors

Cancer Science, Год журнала: 2023, Номер 114(7), С. 2709 - 2721

Опубликована: Май 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.

Язык: Английский

---

WEE1 Inhibition by AZD1775 Augments Colorectal Cancer Cells Susceptibility to VE-822-induced DNA Damage and Apoptosis

Drug Research, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

---

Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Авг. 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

Язык: Английский

---

DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines

Oncology Letters, Год журнала: 2025, Номер 29(3)

Опубликована: Янв. 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.

Язык: Английский

---

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

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 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.

Язык: Английский

---

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

Molecular and Cellular Biology, Год журнала: 2025, Номер unknown, С. 1 - 17

Опубликована: Фев. 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.

Язык: Английский

---

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

European Journal of Medicinal Chemistry Reports, Год журнала: 2025, Номер unknown, С. 100250 - 100250

Опубликована: Фев. 1, 2025

Язык: Английский

---

Locking the gates of immortality: targeting alternative lengthening of telomeres (ALT) pathways

Medical Oncology, Год журнала: 2025, Номер 42(3)

Опубликована: Фев. 18, 2025

Язык: Английский

---

The Development of ATM Inhibitors in Cancer Therapy

Targeted Oncology, Год журнала: 2025, Номер unknown

Опубликована: Март 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

Язык: Английский

---

Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3744 - 3744

Опубликована: Апрель 16, 2025

Transcription-coupled repair (TCR) and R-loops are two interrelated processes critical to the maintenance of genome stability during transcription. TCR, a specialized sub-pathway nucleotide excision repair, rapidly removes transcription-blocking lesions from transcribed strand active genes, thereby safeguarding transcription fidelity cellular homeostasis. In contrast, R-loops, RNA–DNA hybrid structures formed co-transcriptionally, play not only regulatory roles in gene expression replication but can also contribute instability when persistently accumulated. Recent experimental evidence has revealed dynamic crosstalk between TCR R-loop resolution pathways. This review highlights current molecular insights into biology, discusses impact their crosstalk, explores emerging therapeutic strategies aimed at optimizing DNA reducing disease risk conditions such as cancer neurodegenerative disorders.

Язык: Английский

---