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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Recent advancements in nanoconstructs for the theranostics applications for triple negative breast cancer

Journal of Drug Delivery Science and Technology, Год журнала: 2024, Номер 93, С. 105401 - 105401

Опубликована: Янв. 25, 2024

Cancer is a major public health concern worldwide; it the second-highest cause of death in United States. According to projections cancer incidence and mortality rates throughout world for year 2023, triple-negative breast (TNBC) expected be leading related among women worldwide. Traditional strategies treatment TNBC have many drawbacks, such as drug resistance, toxicity etc. Discovering novel delivery techniques researching innovative, efficient methods important. This review discusses types subtypes TNBC. The problems associated with standard therapies, mechanism resistance highlights need develop therapeutic strategies. It provides information on relative prevalence severity cancer. Several approaches viz. targeted therapy, gene bacterial-mediated nanomedicine, immune checkpoint inhibitors, theranostic, radiotherapy, chemotherapy, immunotherapy, herbal AI-based TNBC, are discussed detail. Additionally, diagnostic techniques, including imaging biopsy, expression profiling, mammography, magnetic resonance imaging, ultrasound, computed tomography scan, positron emission immunohistochemistry, been effective treatment. in-depth analysis innovative individualized care serve patients better.

Язык: Английский

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PARP Inhibitors in Breast and Ovarian Cancer

Cancers, Год журнала: 2023, Номер 15(8), С. 2357 - 2357

Опубликована: Апрель 18, 2023

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples clinical translation targeted therapies in medical oncology, and this has been demonstrated by their effective management BRCA1/BRCA2 mutant cancers, notably breast ovarian cancers. PARP target DNA repair pathways that BRCA1/2-mutant tumours dependent upon. Inhibition key components these leads to damage triggering subsequent critical levels genomic instability, mitotic catastrophe cell death. This ultimately results a synthetic lethal relationship between BRCA1/2 PARP, which underpins effectiveness inhibitors. Despite early dramatic response seen with inhibitors, patients receiving them often develop treatment resistance. To date, data from both preclinical studies have highlighted multiple resistance mechanisms only understanding we able overcome challenges. The focus review is summarise underlying underpinning aid clinicians scientists better clinically applicable assays select who would derive greatest benefit as well new novel/combination strategies With inhibitor mechanisms, not be identify subset unlikely therapy but also sequence our paradigm avoid mechanisms.

Язык: Английский

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EZH2 inhibition sensitizes MYC-high medulloblastoma cancers to PARP inhibition by regulating NUPR1-mediated DNA repair

Oncogene, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 19, 2024

Язык: Английский

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If it’s a target, it’s a pan-cancer target: Tissue is not the issue

Cancer Treatment Reviews, Год журнала: 2024, Номер 125, С. 102721 - 102721

Опубликована: Март 21, 2024

Cancer is traditionally diagnosed and treated on the basis of its organ origin (e.g., lung or colon cancer). However, organ-of-origin diagnostics does not reveal underlying oncogenic drivers. Fortunately, molecular have advanced at a breathtaking pace, it increasingly apparent that cancer disease genome. Hence, we now multiple genomic biomarker-based, tissue-agnostic Food Drug Administration approvals for both gene- immune-targeted therapies (larotrectinib/entrectinib, NTRK fusions; selpercatinib, RET dabrafenib plus trametinib, BRAF

Язык: Английский

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PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair

The EMBO Journal, Год журнала: 2024, Номер 43(6), С. 1015 - 1042

Опубликована: Фев. 15, 2024

Abstract Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have poor understanding of the specific genetic vulnerabilities that would make cells susceptible such tailored therapy. Moreover, identification interest for targeting BRCA2;p53-deficient tumors acquired resistance polymerase inhibitors (PARPi) through loss PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, identify genes involved in DNA repair be essential survival PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 major synthetic lethal interactors loss. We provide evidence compromised replication fork progression, single-strand break repair, Okazaki fragment processing cells, alterations exacerbate effects EXO1/FEN1 inhibition become this context. Since sensitivity dependent on BRCA2 defects, propose target PARPi-resistant lost activity. may useful strategy enhancing effect homologous recombination-deficient tumors.

Язык: Английский

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DNA Adducts in Cancer Chemotherapy

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(7), С. 5113 - 5143

Опубликована: Март 29, 2024

DNA adducting drugs, including alkylating agents and platinum-containing are prominent in cancer chemotherapy. Their mechanisms of action involve direct interaction with DNA, resulting the formation addition products known as adducts. While these adducts well-accepted to induce cell death, understanding their specific chemotypes role drug therapy response remain limited. This perspective aims address this gap by investigating metabolic activation chemical characterization formed U.S. FDA-approved drugs. Moreover, clinical studies on potential biomarkers for predicting patient responses efficacy examined. The overarching goal is engage interest medicinal chemists stimulate further research into use guiding personalized treatment.

Язык: Английский

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Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(9), С. 1828 - 1881

Опубликована: Апрель 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Язык: Английский

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CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Июнь 11, 2024

Abstract Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated mediating therapeutic resistance. damage checkpoint kinase 1 (CHK1) integrates cell cycle replicating cells, its inhibition causes replication stress, deficiency dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) proteins (PARylation) subsequent decrease cellular NAD + levels OC cells treated CHK1 inhibitor prexasertib, indicating activation dependent enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are clinical use treating OC, tumor resistance these drugs highly imminent. reasoned that dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt crosstalk overcome chemoresistance. Although PARG (PARGi) trapped PARylation activated CHK1, it did not cause any significant death. However, deficient were hypersensitive PARGi, suggesting a role for protection cells. Correspondingly, combination exhibited excessive stress-mediated lesions, dysregulation, mitotic catastrophe compared individual drugs. Interestingly, increased treatment resulted depletion levels. These decreased also paralleled reduced aldehyde dehydrogenase (ALDH) activity, which requires maintain stem Furthermore, prexasertib PARGi combinations synergistic death including an isogenic chemoresistant line 3D organoid models primary patient-derived lines. Collectively, our data highlight novel between metabolism involving stress -dependent PARylation, suggest therapy chemoresistance OC.

Язык: Английский

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Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1269 - 1269

Опубликована: Окт. 9, 2024

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a damage sensor. It has become promising biological target for anticancer drug studies. Enhanced expression present several types of tumors, such melanomas, lung cancers, breast correlating low survival outcomes resistance to treatment. inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy agents both single drugs sensitizers chemo- radiotherapy. This review explores properties, characteristics, challenges discussing their development from first-generation compounds, more sustainable synthesis methods discovery new anti-cancer agents, mechanisms therapeutic action, potential targeting additional targets beyond catalytic active site proteins. Perspectives on green chemistry also discussed.

Язык: Английский

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