DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities

Experimental & Molecular Medicine, Год журнала: 2022, Номер 54(10), С. 1658 - 1669

Опубликована: Окт. 7, 2022

Abstract Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit growth cancer cells are integral approaches therapy. Although DNA-damaging therapies advance battle with cancer, resistance, recurrence following treatment common. Thus, searching for vulnerabilities facilitate action agents by sensitizing is an active research area. Therefore, it crucial decipher detailed molecular events involved in responses (DDRs) cancer. The tumor suppressor p53 at hub DDR. Researchers have identified increasing number genes regulated transcriptional functions been shown be critical direct or indirect mediators cell fate, cycle regulation, repair. Posttranslational modifications (PTMs) primarily orchestrate activity response damage. Many molecules mediating PTMs identified. anticancer potential realized targeting these has through experiments clinical trials sensitize agents. This review briefly acknowledges complexity DDR pathways/networks. We specifically focus regulators, protein kinases, E3/E4 ubiquitin ligases their potential.

Язык: Английский

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BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside

Cancers, Год журнала: 2022, Номер 14(16), С. 3888 - 3888

Опубликована: Авг. 11, 2022

DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian (EOC) is among the tumours with highest percentage of hereditary cases. BRCA1 BRCA2 predisposing pathogenic variants (PVs) were first to associated EOC, whereas additional genes comprising homologous recombination (HR) pathway have been discovered sequencing technologies. The incidence DDR patients metastatic prostate much higher compared those localized disease. Genetic testing playing an increasingly important role treatment cancer. development poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for EOC. One mechanisms PARP exploits concept synthetic lethality. Tumours or mutations highly sensitive inhibitors. Moreover, lethal interaction may beyond germline BRCA context HR deficiency, this area ongoing research. advanced stages as castration-resistant However, there major concern regarding need identify reliable biomarkers predictive response. In review, we explore DDR, potential genomic analysis cancer, therapeutics inhibitors, along biomarkers.

Язык: Английский

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Targeting the BRCA1/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Март 22, 2023

BRCA1 and BRCA2 play a critical role in variety of molecular processes related to DNA metabolism, including homologous recombination mediating the replication stress response. Individuals with mutations ( BRCA1/2 ) genes have significantly higher risk developing various types cancers, especially cancers breast, ovary, pancreas, prostate. Currently, Food Drug Administration (FDA) has approved four PARP inhibitors (PARPi) treat mutations. In this review, we will first summarize clinical outcomes FDA-approved PARPi treating deficient cancers. We then discuss evidence supporting hypothesis that cytotoxic effect is likely due inducing excessive at difficult-to-replicate (DTR) genomic regions mutated tumors. Finally, ongoing preclinical studies on how combine immuno-oncology drugs further improve outcomes.

Язык: Английский

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Leveraging NKG2D Ligands in Immuno-Oncology

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Июль 29, 2021

Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards development novel assets to achieve durable immune control cancer. Yet, presence tumor evasion mechanisms represents a challenge for efficient treatment options. Therefore, combination therapies are taking center stage in immuno-oncology. Such should boost anti-tumor responses and/or target escape mechanisms, especially those created by major players microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at forefront many immunotherapy strategies, several approaches being designed fully exploit NK cell antitumor potential. One most relevant cell-activating receptors is NKG2D, receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA MICB. MICB poorly expressed on normal but become upregulated surface damaged, transformed or infected result post-transcriptional post-translational intracellular pathways. Their engagement triggers effector functions. Also, MICA/B polymorphic polymorphism affects functional through regulation their cell-surface expression, trafficking, shedding soluble immunosuppressive isoforms, affinity interaction. Although immunotherapeutic NKG2D-NKG2DL axis under investigation, account reduced expression NKG2DL contribute escape. determines NKG2D-dependent responses, thus representing an additional leveraging In this review, we discuss strategies inhibit propose with antibodies aimed promoting upregulation reprograming TAM into pro-inflammatory remodeling TME, emerge frontrunners because they may unleash functions cytotoxic CD8 T (CTL). Pursuing these pipelines might lead innovative modalities wide range cancer patients.

Язык: Английский

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It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Янв. 26, 2022

Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies’ greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from research community. Among them, MDM2 ARF considered most influential p53 regulators due their abilities inhibit activate functions, respectively. inhibits promoting ubiquitination proteasome-mediated degradation while activates physically interacting with block its access p53. This conventional understanding p53-MDM2-ARF functional triangle guided direction research, as well development p53-based therapeutic strategies for last 30 years. Our increasing knowledge this during time, especially through identification p53-independent functions ARF, uncovered many under-appreciated molecular connecting these three proteins. Through recognizing both antagonizing synergizing relationships among consideration harnessing develop effective therapies needs an update accordingly. In review, we will re-visit wisdom regarding tumor-regulating mechanisms, highlight impactful studies contributing modern look relationships, summarize ongoing efforts target pathway treatments. A refreshed appreciation network can bring innovative approaches new generations genetically-informed clinically-effective therapies.

Язык: Английский

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Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism

Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(19), С. 13198 - 13215

Опубликована: Сен. 20, 2022

DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor human Polθ (encoded by POLQ). A high-throughput screening campaign 350,000 compounds identified 11 micromolar hit, giving rise the N2-substituted fused pyrazolo series, which was validated biophysical methods. Structure-based design along with optimization cellular potency ADME ultimately led identification RP-6685: potent, selective, orally bioavailable that showed vivo efficacy HCT116 BRCA2–/– mouse tumor xenograft model.

Язык: Английский

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PBRM1, SETD2 and BAP1 — the trinity of 3p in clear cell renal cell carcinoma

Nature Reviews Urology, Год журнала: 2022, Номер 20(2), С. 96 - 115

Опубликована: Окт. 17, 2022

Язык: Английский

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PARP Inhibitor Insensitivity to BRCA1/2 Monoallelic Mutations in Microsatellite Instability-High Cancers

JCO Precision Oncology, Год журнала: 2022, Номер 6

Опубликована: Июнь 1, 2022

PURPOSE To examine the overlap of homologous recombination deficiency (HRD) and microsatellite instability high (MSI-H) status, to dissect driver versus bystander status BRCA1/2 mutations ( BRCAm) in this context. METHODS A pan-cancer comprehensive genomic profiling cohort (n = 213,199) was examined for between BRCAm MSI-H status. variant zygosity correlated with tumor mutational burden, genome-wide loss heterozygosity (gLOH). Clinical histories two patients prostate cancer co-occurring are described. RESULTS HRD phenotypes were generally mutually exclusive events P < .001). that co-occurred together burden or predominantly monoallelic alterations. In breast, ovarian, pancreatic cancers, very few occurred context MSI-H; however, cancer, 12.8% BRCA1 3.4% BRCA2 alterations MSI-H. these BRCA-associated not associated elevated gLOH. Two showed resistance poly (ADP-ribose) polymerase inhibition but sensitivity subsequent anti–programmed cell death protein 1 therapy. CONCLUSION phenomena across types, may rarely co-occur, especially cancer. Although samples had a higher prevalence relative microsatellite-stable tumors, Our findings suggest most coexisting likely result inhibitors.

Язык: Английский

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Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(23), С. 17413 - 17435

Опубликована: Ноя. 23, 2021

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast susceptibility gene (BRCA) mutation. Inducing deficiency homologous recombination (HR) repair an effective way to broaden indication PARP1/2 inhibitor more patients cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported elevate HR deficiency. Therefore, we designed, synthetized, and optimized dual PARP/BRD4 III-16, completely new structure high selectivity against BRD4. III-16 showed favorable synergistic antitumor efficacy in cells xenografts by arresting cell cycle progression, inhibiting DNA damage repair, promoting autophagy-associated death. Moreover, reversed Olaparib-induced acceleration progression recovery repair. The advantages over Olaparib suggest that inhibitors are novel agents advanced

Язык: Английский

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