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12 recordsLinked to original sources
PubMed2026

Discovery of novel quinazoline-containing ATR inhibitor for treatment of acute myeloid leukemia.

ATR is a core kinase in the DNA damage response pathway, primarily sensing replication pressure and double strand breaks, initiating cell cycle arrest, DNA repair, and apoptosis programs, and maintaining genomic stability. In this work, we validated that intervention in ATR function might regulate the progression of AML through bioinformatics analysis. And a series of novel ATR inhibitors based on quinazoline moiety were obtained. The promising compound C7 achieved effective enzyme level and cellular level inhibitory activities, and exhibited acceptable liver S9 stability and oral bioavailability, with no high risk of drug-drug interactions. Research on the underlying mechanism indicated that compound C7 could inhibit the development of MOLM-13 through a dual mechanism of rapidly inducing cell apoptosis and exacerbating DNA damage levels. In brief, compound C7 might be a promising candidate or lead compound for the discovery of novel ATR inhibitors and the treatment of AML.

Quinazolines↗
PubMed2026

Loss of BOK increases vulnerability of p53 deficient non-small cell lung cancer cells to ATR inhibition through its role in uridine metabolism.

BOK is a pro-apoptotic member of the BCL-2 family frequently repressed in cancer and with emerging roles beyond apoptosis. BOK interacts with and increases uridine monophosphate synthetase (UMPS) activity, thereby promoting uridine monophosphate (UMP) synthesis. We previously showed that BOK protein is downregulated in primary human lung cancer samples, correlating with poorer patient survival. Here, we demonstrate that BOK deficiency increases DNA damage, triggering p53 activation and cell cycle arrest in two independent non-small cell lung cancer (NSCLC) cell models that express either WT or defective p53. In a p53-deficient setting, BOK loss caused elevated baseline DNA damage rendering cells more dependent on alternative DNA repair pathways. We exploited this vulnerability by inhibiting the ATR-mediated DNA damage response pathway with the selective ATR inhibitor ceralasertib (AZD6738). ATR inhibition in BOK/p53 compound-deficient NSCLC cells exacerbated DNA damage and induced cell death, indicating a synthetic lethal interaction. The DNA damage in BOK-deficient cells was rescued by a cell permeable BOK-BH3-derived peptide, confirming the mechanistic link between BOK and UMPS. Taken together, our findings reveal a vulnerability in NSCLC, where combined loss of p53 and BOK sensitises cells to ATR inhibition. This synthetic interaction suggests that p53-deficient tumours with reduced BOK expression may be more reliant on ATR-mediated DNA repair, providing a mechanistic basis for their susceptibility to ATR inhibitors. Given the frequent inactivation of p53 in lung cancer, our study offers a rationale for clinical exploration of ATR inhibitors, in combination with standard chemotherapy, in the context of reduced BOK function. Future investigations into the broader role of BOK in genomic stability and nucleotide metabolism may uncover additional therapeutic strategies for cancers with repressed BOK.

Humans↗
PubMed2025

Clinicopathologic and Genomic Characterization of SMARCA4-Deficient Carcinoma of the Gallbladder.

As a key subunit of the SWItch/sucrose nonfermentable chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA4-deficient carcinoma of the gallbladder (SMARCA4-dGBC) have not been well explored. In this study, a retrospective cohort of 926 nonsquamous cell gallbladder carcinomas (GBCs) was analyzed on tissue microarrays using immunohistochemistry for SMARCA4, comprising 813 adenocarcinomas, 53 adenosquamous carcinomas, 43 undifferentiated carcinomas, 7 sarcomatoid carcinomas, 6 small cell neuroendocrine carcinomas, and 4 large cell neuroendocrine carcinomas. Twenty-six (2.8%) SMARCA4-dGBCs were identified and further analyzed using immunohistochemistry, whole-exome sequencing, and clinicopathological data. SMARCA4-dGBCs are frequently identified in advanced stages and exhibit diverse patterns of differentiation. The majority were identified as monotonous diffuse sheets, nests, and cords, whereas a subset exhibited gland-forming and rhabdoid morphologies (11.5%). Tumors retained mismatch repair proficiency (100%) but showed variable HER2 expression (11.5% scored as 2+/3+) and limited PD-L1 positivity. Genomic profiling revealed SMARCA4 alterations in 88.5% (23/26) of patients, predominantly deletions (91.3%) and truncating mutations-p.K892∗ and p.R979∗-that disrupt the critical ATPase/helicase domains. Co-occurring TP53 mutations (56.5%) highlighted the presence of synergistic chromatin-remodeling defects. Enrichment of oncogenic signaling pathways, including the RTK-RAS (78.3%), TP53 (60.9%), NOTCH (47.8%), and HIPPO (39.1%) pathways, was observed. Patients with SMARCA4-dGBC exhibited significantly shorter progression-free survival (median, 6 vs 14 months) and overall survival (median, 11 vs 16 months) than those with SMARCA4-retained tumors. Overall, these findings revealed that SMARCA4-dGBC is a rare, distinct entity characterized by the destabilization of the SWItch/sucrose nonfermentable complex, genomic instability, and resistance to conventional therapies. The prevalence of targetable pathways, such as RTK-RAS and cell cycle dysregulation, highlights opportunities for precise therapeutic strategies involving EZH2, CDK4/6, or ATR inhibitors. SMARCA4 immunohistochemistry and molecular profiling are essential for accurate diagnosis, prognostic stratification, and therapeutic innovation of this GBC subtype.

Humans↗
PubMed2025

The Role of Homologous Recombination Deficiency (HRD) in Renal Cell Carcinoma (RCC): Biology, Biomarkers, and Therapeutic Opportunities.

Renal Cell Carcinoma (RCC) is a common malignancy, often diagnosed incidentally. In recent years, the prognosis of metastatic disease has been improved due to the development of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) as first-line treatments. However, when progression occurs, the therapeutic options are limited. Understanding crucial biological pathways could lead to a greater understanding of the natural history of the disease, which could help to overcome the mechanism of resistance and to develop new treatments. The clinical significance of homologous recombination deficiency (HRD) in RCC remains to be investigated. To improve the knowledge about this topic, we conducted a narrative review to summarize the current evidence on HRD-related variations and signatures in RCC, together with their prognostic and predictive implications. Preliminary evidence indicates that canonical HRD variants (BRCA1/2) are infrequent in RCC, while broader DNA damage response (DDR) alterations like BAP1, PBRM1, ATM, and SETD2 are more prevalent. Elevated HRD genomic scores in clear-cell RCC correlate with a worse prognosis and an immunologically exhausted microenvironment. From a therapeutic point of view, PARP inhibitor monotherapy has exhibited initial efficacy in small cohorts with high levels of DDR mutation, yet remains investigational for RCC.

Humans↗
PubMed2026

Deconstructing the Alternative Lengthening of Telomeres: Integromics Prioritizes Five Master Hubs Dictating Clinical Survival and Therapeutic Vulnerabilities.

The Alternative Lengthening of Telomeres (ALT) pathway drives replicative immortality in aggressive malignancies, particularly sarcomas and gliomas. Clinical ALT stratification has relied on screening for structural ATRX and DAXX mutations. However, this genotypic approach fails to capture the dynamic macro-reprogramming required to sustain ALT. Here, we established and validated a 28-gene transcriptomic signature that captures the ALT-associated transcriptomic phenotype of the ALT phenotype. Using multivariate Cox proportional hazards models and time-dependent ROC analyses, we demonstrate that this signature is a robust, independent predictor of poor overall survival in Sarcoma (SARC) and Lower Grade Glioma (LGG) cohorts, outperforming the prognostic value of traditional ATRX/DAXX mutational status. Genomic mapping revealed this transcriptional synchrony is structurally facilitated by non-random focal clustering on Chromosome 8. To deconstruct the machinery driving this lethal phenotype, we employed an integromic approach, synthesizing protein-protein and metabolic flux networks. Topological algorithms prioritized five indispensable hubs: TP53, ATM, ATR, PCNA, and UBE2I. Gene-metabolite profiling identified PCNA as a bottleneck funneling extreme deoxyribonucleotide (dNTP) demand to sustain break-induced telomeric recombination. To translate these vulnerabilities into actionable treatments, we mapped these hubs to a precision pharmacological network. We propose a multi-targeted strategy combining FDA-approved PARP inhibitors to exploit ATR-mediated synthetic lethality, alongside antimetabolites to induce nucleotide starvation. This study redefines ALT risk stratification and provides a data-driven framework to target and treat resistant ALT-positive tumors.

Alternative Lengthening of Telomeres↗
PubMed2026

ATR-dependent phosphorylation of the histone acetyltransferase HBO1 suppresses chromatin binding and promotes replication stress responses.

Mounting evidence has shown that histone acetyltransferase binding to ORC1 (HBO1) serves as an oncoprotein, warranting the use of the small molecule inhibitor WM-3835 for cancer therapy. However, HBO1 is ubiquitously expressed in both tumor and normal tissues, with potential to increase the risk of systemic toxicity. This unmet need highlights the importance of identifying suitable biomarkers to predict the sensitivity to HBO1 inhibitor. Here, we show that ATR, a key regulator of DNA replication stress, is a novel interacting partner of HBO1. In addition, we reveal a regulatory function of HBO1 in DNA replication stress responses, in an ATR-dependent manner. Mechanistically, ATR mediated HBO1 Ser50/53 phosphorylation interferes with the genomic binding of HBO1 and regulates gene expression. Notably, overexpression of HBO1 mutated at the ATR phosphorylation site (S50/53A) dampens the expression of DNA repair related genes and suppresses tumor colony formation, consistent with the observations of WM-3835 treatment. Inhibition of ATR significantly antagonized the sensitivity to WM-3835 treatment. Collectively, our findings uncovered a previously unidentified role of HBO1 in the regulation of replication stress and discovered ATR as a potential biomarker for WM-3835 treatment.

ATR↗
PubMed1977

Spin-labeled acyl atractyloside as a probe of the mitochondrial adenosine diphosphate carrier. Asymmetry of the carrier and direct lipid environment.

A number of spin-labeled acyl derivatives of atractyloside, (m,n)acyl-ATR (general formula: CH3- (CH2)mCX(CH2)nCOO-ATR, where X is an o-azolidine ring containing a nitroxide), have been synthesized. As shown by electron spin resonance (ESR) spectra of spin-labeled acyl-ATR, the nitroxide placed on the acyl chain interacts with the diterpene residue of the atractyloside moiety when incorporated in liposomes. Spin-labeled acyl-ATRs were used to probe the ADP carrier in heart mitochondria. They inhibit ADP transport with the same efficiency as unlabeled acyl-ATRs. The inhibition is a mixed competitive and noncompetitive inhibition. The inhibitor constant is close to 10(-7) M. The long chain acyl-ATRs (10,3)- (7,6)-, (7,8)-, and (5,10)acyl-ATRs) and also the short chain (0,2)acyl-ATR, when added at low concentrations to heart mitochondria, give rise to more immobilized ESR spectra than when added to liposomes. Immobilization is stronger for the first three molecules of the series. The (1,14)acyl-ATR, which possesses a nitroxide almost at the end of the acyl chain near the terminal methyl, gives rise to a spectrum corresponding to a high degree of fluidity. Upon addition of atractyloside or of other specific ligands, spin-labeled long-chain acyl-ATRs bound to the ADP carrier are displaced from their binding site toward the lipid phase of the mitochondrial membrane and the short chain (0,2)acyl-ATR is released into the aqueous phase. Spin-labeled long-chain acyl-ATRs do not show any evidence of binding to a protein when incubated with "inside out" submitochondrial particles, in spite of the fact that these particles are able to transport ADP. These results are discussed with respect to the size and the asymmetry of the ADP carrier in the mitochondrial membrane and the mechanism of ADP transport.

Adenosine Diphosphate↗
PubMed2026

Chemogenomic maps reveal a PRDX1-dependent iron-damage axis in the DNA damage response.

The DNA damage response (DDR) is a sophisticated network of cellular pathways whose perturbation leads to genome instability and is a key hallmark of oncogenesis. Here, we present data from 32 genome-scale loss-of-function CRISPR interference chemical-genetic screens with inhibitors targeting core constituents of the DDR machinery (PARP, ATR, ATM, DNAPK and WEE1), as both single agents and in combination with poly(ADP-ribose) polymerase inhibitors. These experiments identify >1,000 genes whose perturbation modifies the DDR and provides a rich resource to the DDR community. In addition, this compendium of functional genomics data reveals key principles governing the DDR and highlights a strong chemical-genetic interaction between loss of activity of the peroxiredoxin PRDX1 and all tested DDR inhibitors through a mechanism involving iron availability mediated by an MRGBP-PAX7-IREB2 axis. Our data position PRDX1 as a key suppressor of DNA damage accumulation and potential druggable target in combination with DDR inhibitors.

Journal Article↗
PubMed2026

Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours.

ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.

Humans↗
PubMed2026

PARG inhibition reduces ssDNA levels and limits RPA loading upon replication fork collapse.

Poly(ADP-ribosyl)ation (PARylation) is a transient post-translational modification catalyzed by PARP enzymes and reversed by PARG. PARG inhibition causes sustained PARylation and is being explored as an anticancer strategy, but its cellular consequences remain incompletely understood. Here, we examine how persistent PARylation influences cellular responses to replication stress and DNA damage. We show that sustained PARylation reduces phosphorylated and chromatin-bound RPA most strongly under fork-stalling conditions that progress toward fork collapse. This effect requires PARP1 activity and is restrained by intact ATR-CHK1 signaling, as checkpoint inhibition renders otherwise resistant cells permissive for PARG inhibitor-associated phosphorylated RPA loss from the chromatin. The reduction of RPA phosphorylation is not dependent on BRCA1 and it is not accompanied by increased RAD51 loading. Instead, reduced chromatin-bound RPA coincides with decreased exposed ssDNA. Our results identify a checkpoint-dependent fork-collapse state in which sustained PARylation limits ssDNA and RPA levels.

Replication Protein A↗
PubMed2023

RNF4 and USP7 cooperate in ubiquitin-regulated steps of DNA replication.

DNA replication requires precise regulation achieved through post-translational modifications, including ubiquitination and SUMOylation. These modifications are linked by the SUMO-targeted E3 ubiquitin ligases (STUbLs). Ring finger protein 4 (RNF4), one of only two mammalian STUbLs, participates in double-strand break repair and resolving DNA-protein cross-links. However, its role in DNA replication has been poorly understood. Using CRISPR/Cas9 genetic screens, we discovered an unexpected dependency of RNF4 mutants on ubiquitin specific peptidase 7 (USP7) for survival in TP53-null retinal pigment epithelial cells. TP53-/-/RNF4-/-/USP7-/- triple knockout (TKO) cells displayed defects in DNA replication that cause genomic instability. These defects were exacerbated by the proteasome inhibitor bortezomib, which limited the nuclear ubiquitin pool. A shortage of free ubiquitin suppressed the ataxia telangiectasia and Rad3-related (ATR)-mediated checkpoint response, leading to increased cell death. In conclusion, RNF4 and USP7 work cooperatively to sustain a functional level of nuclear ubiquitin to maintain the integrity of the genome.

Animals↗
PubMed2026

Replication stress links Geminin depletion to centrosome amplification.

The timing of DNA replication and centrosome duplication is tightly regulated with cell cycle progression to ensure the faithful duplication of the genome during cell division. Both DNA and centrosomes are licensed for replication in late telophase/early G1, replicated in S phase and segregated during mitosis; yet how defects in DNA replication licensing are coupled to centrosome homeostasis remains poorly understood. Here, we show that depletion of the replication licensing inhibitor Geminin in proliferating mouse embryonic fibroblasts induces robust centrosome amplification together with impaired primary cilium assembly. Rather than promoting whole-genome reduplication, knockdown of Geminin triggers a replication stress response, characterized by DNA damage accumulation throughout the cycle, and activation of an ATR-dependent DNA damage response. Mechanistically, Geminin depletion-induced replication stress activates the ATR-Chk1-Wee1 checkpoint axis prolonging G2 and leading to premature centriole disengagement and centrosome amplification. These findings identify replication stress as the signaling module that couples defective DNA replication licensing to centrosome amplification.

DNA damage↗