Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism

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

Published: Feb. 1, 2025

Language: Английский

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PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer

Cancer Research, Journal Year: 2021, Volume and Issue: 81(11), P. 2888 - 2902

Published: April 22, 2021

Abstract Inactivation of Polybromo 1 (PBRM1), a specific subunit the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% clear cell renal carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used series orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor lethality was recapitulated using several clinical vitro model systems vivo xenograft ccRCC. In absence exogenous DNA damage, cells exhibited elevated levels replication stress, micronuclei, R-loops. exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed multiple R-loop processing factors were downregulated tumor cells. Exogenous expression resolution enzyme RNase H1 reversed sensitivity PBRM1-deficient inhibitors, suggesting excessive R-loops could be cause this lethality. also induced cyclic GMP-AMP synthase/stimulator interferon genes (cGAS/STING) innate immune signaling Overall, findings provide preclinical basis for cancers. Significance: This study demonstrates are loss PBRM1, PBAF-specific subunit, thus providing rationale assessing patients cancer.

Language: Английский

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Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial

Annals of Oncology, Journal Year: 2021, Volume and Issue: 32(12), P. 1590 - 1596

Published: Sept. 11, 2021

Language: Английский

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Optimizing cisplatin delivery to triple-negative breast cancer through novel EGFR aptamer-conjugated polymeric nanovectors

Journal of Experimental & Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 40(1)

Published: July 22, 2021

Abstract Background Management of triple-negative breast cancer (TNBC) is still challenging because its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches the metastatic setting, but use by scarce bioavailability, severe systemic side effects drug resistance. Novel site-directed aptamer-based nanotherapeutics have potential to overcome obstacles chemotherapy. In this study we investigated tumor targeting anti-tumorigenic effectiveness novel cisplatin-loaded aptamer-decorated nanosystems TNBC. Methods Nanotechnological procedures were applied entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that conjugated on their surface with epidermal growth factor receptor (EGFR) selective cell-internalizing CL4 aptamer improve therapy. Internalization TNBC MDA-MB-231 BT-549 cells PNPs, loaded BODIPY505-515, was monitored confocal microscopy using EGFR-depleted as negative control. Tumor biodistribution evaluated fluorescence reflectance imaging upon intravenously injection Cyanine7-labeled nanovectors nude mice bearing subcutaneous tumors. Cytotoxicity PNPs toward MTT assay antitumor effect assessed experiments vivo ex analyses. Results We demonstrate specific, rapid uptake EGFR-positive CL4-conjugated fluorescent which, when cisplatin, resulted considerably more cytotoxic than free either unconjugated or scrambled aptamer. Importantly, animal studies showed CL4-equipped achieve significantly higher efficiency enhanced therapeutic effects, without any signs toxicity, compared untargeted PNPs. Conclusions Our proposes safe drug-loaded for excellent application diagnosis

Language: Английский

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Therapeutic and prognostic insights from the analysis of cancer mutational signatures

Trends in Genetics, Journal Year: 2021, Volume and Issue: 38(2), P. 194 - 208

Published: Sept. 2, 2021

Mutational signatures have revolutionized our understanding of cancer etiology by identifying biological processes underlying somatic mutagenesis.Mutational can also represent biomarkers indicative therapy sensitivity, prognosis, and contraindications. Importantly, mutational provide predictive information independent known clinical molecular biomarkers.New technologies increased the feasibility measuring in a cost-effective manner, which may facilitate integration signature analysis into decision-making. The mutations each genome are caused multiple processes, leaves characteristic imprint (or 'signature'), potentially specific etiologies or exposures. Deconvolution these offers glimpse evolutionary history individual tumors. Recent work has shown that yield therapeutic prognostic insights, including identification cell-intrinsic as drug response prognosis. For example, indicating homologous recombination deficiency associated with poly(ADP)-ribose polymerase (PARP) inhibitor whereas APOBEC-associated ataxia telangiectasia Rad3-related kinase (ATR) sensitivity. Furthermore, therapy-induced implicated progression been uncovered, thiopurine-induced TP53 leukemia. In this review, we explore various ways reveal new thus extending their traditional role disease etiology.

Language: Английский

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Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification

Cancer Research, Journal Year: 2022, Volume and Issue: 82(8), P. 1646 - 1657

Published: Feb. 16, 2022

Abstract PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and breast, prostate, pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker HRR functionality, we previously established test to detect foci. Here, aimed validate the score cut off compare performance this other deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, PaC were developed evaluated their response PARPi cisplatin. HRD these patient samples was by DNA sequencing genes, genomic tests, detection. We patient-derived xenograft (n = 103), HGSOC 4), 2) that recapitulated status treatment response. The showed higher accuracy than gene mutations analysis predicting (95%, 67%, 71%, respectively). captured dynamic changes upon acquisition resistance. similar platinum predefined validated, high predictive value preclinical confirmed. These results collectively support pursuing clinical assessment randomized trials testing or platinum-based therapies. Significance: This work demonstrates histopathology-based based on

Language: Английский

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Exploiting synthetic lethality to target BRCA1/2-deficient tumors: where we stand

Oncogene, Journal Year: 2021, Volume and Issue: 40(17), P. 3001 - 3014

Published: March 14, 2021

Language: Английский

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Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: June 17, 2022

Homologous recombination (HR) is a highly conserved DNA repair mechanism that protects cells from exogenous and endogenous damage. Breast cancer 1 (BRCA1) breast 2 (BRCA2) play an important role in the HR pathway by interacting with other proteins such as Fanconi anemia (FA) proteins, ATM, RAD51, PALB2, MRE11A, RAD50, NBN. These pathways are frequently aberrant cancer, leading to accumulation of damage genomic instability known homologous deficiency (HRD). HRD can be caused chromosomal subchromosomal aberrations, well epigenetic inactivation tumor suppressor gene promoters. Deficiency one or more genes increases risk many malignancies. Another involved single-strand breaks (SSBs) base excision repair, which poly (ADP-ribose) polymerase (PARP) enzymes role. PARP inhibitors (PARPIs) convert SSBs cytotoxic double-strand breaks, repaired HR-proficient cells, but remain unrepaired HRD. The blockade both basis PARPI therapy. use PARPIs expanded sporadic cancers displaying "BRCAness" phenotype. Although effective cancers, their efficacy limited development resistance. In this review, we summarize prevalence due mutation, loss heterozygosity, promoter hypermethylation 35 ovarian, breast, colorectal, pancreatic, non-small cell lung prostate cancer. underlying mechanisms strategies overcome resistance also discussed.

Language: Английский

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Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer

JAMA Oncology, Journal Year: 2022, Volume and Issue: 8(12), P. 1802 - 1802

Published: Oct. 27, 2022

Importance Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP with radiotherapy in patients TNBC would enhance the biological effectiveness of irradiation and improve locoregional control is unclear. Objective To assess safety tolerability inhibition olaparib concurrently residual disease after neoadjuvant chemotherapy. Design, Setting, Participants This phase 1 prospective dose-escalation trial (Olaparib Radiation Therapy for [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 November 2019, follow-up until 2021. had an incomplete pathologic response chemotherapy or unresectable despite previous chemotherapy, Eastern Cooperative Oncology Group Performance Status score 0 1, adequate organ functions. Interventions Olaparib administered orally form tablets given at increasing doses (50 mg, 100 150 200 mg twice daily). therapy started week before continued concomitantly radiotherapy. After breast-conserving surgery, total dose 50.4 Gy delivered whole breast, 63-Gy simultaneously integrated boost tumor bed younger than 60 years. radical mastectomy tumors 50.0 chest wall (after mastectomy) (for tumors). Regional lymph node stations could be treated cases node-positive disease. Main Outcomes Measures outcomes were early-stage, high-risk TNBC. Secondary included overall survival (OS) event-free (EFS). Results Among 24 (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects observed, escalated daily without reaching maximum tolerated dose. No late treatment-related grade 3 greater effect observed 2-year 2 pain, fibrosis, deformity patient (4.2%). Three-year OS EFS 83% (95% CI, 70%-100%) 65% 48%-88%), respectively. Homologous recombination status not associated EFS. Conclusions Relevance The findings this suggest that well should continue evaluated further clinical trials. Trial Registration ClinicalTrials.gov Identifier: NCT03109080

Language: Английский

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Deep learning identifies morphological patterns of homologous recombination deficiency in luminal breast cancers from whole slide images

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(12), P. 100872 - 100872

Published: Dec. 1, 2022

Language: Английский

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