A Comprehensive Review on PARP Inhibitors in Targeted Therapy for Cancers DOI Creative Commons

Mounika Guduri,

Samyuktha Kolluru,

Haritha Pasupulati

et al.

Deleted Journal, Journal Year: 2024, Volume and Issue: 19(2), P. 44 - 59

Published: Aug. 9, 2024

The poly (ADP-ribose) polymerase (PARP) family of enzymes involves and regulates various cellular processes essential functions, such as apoptosis, transcription process, DNA repair. PARPs (PARP-1, PARP-2, PARP-3) are a branch familiar proteins that play crucial role in repairing damage human gene involved different cancers regulate the base excision repair (BER) pathway. As target-based drug therapy for cancer, inhibition PARP stops PARP-1 -2 from damaged mutated cancer cells, eventually, cells die. Considering limited available therapies treatment advanced recurrent cancers, inhibitors (PARPi) first approved drugs particularly target response to BRCA (BReast CAncer gene)-1/2 ovarian, pancreatic, prostate, breast cancers. Recently, six PARPi viz., olaparib, rucaparib, niraparib, talazoparib, fuzuloparib, pamiparib were monotherapy or combination with other classes anticancer agents maintenance Moreover, appears improve progression-free survival women platinum-sensitive ovarian an adjuvant conventional treatment. Importantly, use management germline BRCA1/2-associated is novel therapeutic strategy, representing successful targeted improving outcomes patients hereditary Although resistance these has been reported recently, however, strategies have employed overcome sensitivity breast, gastric, prostate

Language: Английский

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets DOI Open Access
Alvina I. Khamidullina, Yaroslav E. Abramenko, Alexandra V. Bruter

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1263 - 1263

Published: Jan. 19, 2024

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision replication for fast proliferation and increased genomic instability. To overcome the consequences improper control, malignant frequently inactivate parts their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other which help maintain fork stability (ATR-CHK1). This creates dependency remaining DDR pathways, vulnerability further destabilization synthetic lethality inhibitors with common oncogenic alterations such mutations TP53, RB1, ATM, amplifications MYC, CCNE1 others. The RS normally limited by coordination cell cycle, transcription replication. Inhibition WEE1 PKMYT1 kinases, prevent unscheduled mitosis entry, leads fragility under-replicated sites. Recent evidence also shows that inhibition Cyclin-dependent kinases (CDKs), CDK4/6, CDK2, CDK8/19 CDK12/13 can contribute through disruption repair control. Here, we review main causes in cancers well therapeutic targets—ATR, CHK1, PARP inhibitors.

Language: Английский

Citations

21
Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke DOI
Yang Liu,

Lauren Guttman,

Valina L. Dawson

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116174 - 116174

Published: March 27, 2024

Language: Английский

Citations

12
PARP1 at the crossroad of cellular senescence and nucleolar processes DOI

Kinga Kołacz,

Agnieszka Robaszkiewicz

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 94, P. 102206 - 102206

Published: Jan. 24, 2024

Language: Английский

Citations

8
The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy DOI Creative Commons

Meiyi Ge,

Jian Luo,

Yi Wu

et al.

MedComm – Oncology, Journal Year: 2024, Volume and Issue: 3(1)

Published: March 1, 2024

Abstract Synthetic lethality (SL), a genetic concept, has revolutionized the development of antitumor therapies by providing avenues to target previously “undruggable” targets with enhanced specificity for tumor cells over normal tissue. The principles SL have expanded beyond definitions encompass biological functions, including genome stability, cell cycle regulation, death mechanisms, cellular metabolism, cell–cell interactions, and microenvironment (TME). Tumor inactivated survival pathways are sensitive therapeutic inhibition compensatory while remain unaffected. Exploiting based on functional contexts potential significantly improve cancer patient reducing resistance targeted enhancing efficacy when combined other treatment modalities. This review explores underlying mechanisms synthetic interactions (SLI) characterized functions in individual TME. We also provide comprehensive summary strategies leveraging dynamic nature SLI overcome resistance. Additionally, we discuss various approaches models screening designing potent agents tailored specific needs patients, as well combining drugs treatment. offers valuable insights into harnessing promising avenue precision therapy.

Language: Английский

Citations

8
Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers DOI Creative Commons
Brant Gracia,

Patricia Montes,

Angelica M. Gutierrez‐Barrera

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113803 - 113803

Published: Feb. 1, 2024

Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity human carriers confound predictions. Here, we elucidate protein folding as a cellular mechanism driving mutation tumor suppressor BRCA1. Using high-throughput protein-protein interaction assay, show that protein-folding chaperone binding patterns predict pathogenicity variants BRCA1 C-terminal (BRCT) domain. HSP70 selectively binds 94% pathogenic BRCA1-BRCT variants, most which engage more than HSP90. Remarkably, magnitude linearly correlates with loss function. We identify prevalent class hypomorphic bind moderately to chaperones retain partial Furthermore, signifies greater penetrance earlier onset clinic. Our findings demonstrate utility quantitative biosensors variant folding, phenotypic severity, risk.

Language: Английский

Citations

7
Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors DOI Creative Commons

Gyöngyvér Szentmártoni,

Dorottya Mühl,

Renata Csanda

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 593 - 593

Published: March 6, 2024

Ten percent of patients with breast cancer, and probably somewhat more in ovarian have inherited germline DNA mutations the cancer genes BRCA1 BRCA2. In remaining cases, disease is caused by acquired somatic genetic epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), emerged treating cancers associated BRCA since 2014. The first PARPi was FDA-approved initially for mutations. Deleterious variants BRCA1/BRCA2 homologous recombination deficiency status been strong predictors response to a few solid tumors then. However, relevance less clear. Somatic BRCA-mutated might also respond this new class therapeutics. Although related literature often controversial, recently published case reports and/or randomized studies demonstrated effectiveness aim review summarize predictive role provide further assistance clinicians identification who could potentially benefit from PARPi.

Language: Английский

Citations

6
Metabolic vulnerabilities in cancer: A new therapeutic strategy DOI
Mohamed El‐Tanani, Syed Arman Rabbani,

Yahia El‐Tanani

et al.

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 201, P. 104438 - 104438

Published: July 6, 2024

Language: Английский

Citations

5
Combining [177Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer DOI Creative Commons
Hartmut Rauch, Carolin Kitzberger, Kirti Janghu

et al.

European Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2024, Volume and Issue: 51(13), P. 4099 - 4110

Published: July 18, 2024

Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), significant clinical benefit of SSTR2-targeted radionuclide therapies was not observed so far. We hypothesize that combination treatment PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness therapy in SCLC.

Language: Английский

Citations

5
Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors DOI
Shaobin Wang, Chao Wang, Jinxin Liu

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 103, P. 117662 - 117662

Published: March 6, 2024

Language: Английский

Citations

4
Integration of machine learning and experimental validation to identify the prognostic signature related to diverse programmed cell deaths in breast cancer DOI Creative Commons

Longpeng Li,

Jinfeng Zhao, Yaxin Wang

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: Jan. 6, 2025

Programmed cell death (PCD) is closely related to the occurrence, development, and treatment of breast cancer. The aim this study was investigate association between various programmed patterns prognosis cancer (BRCA) patients. levels 19 different deaths in were assessed by ssGSEA analysis, these PCD scores summed obtain PCDS for each sample. relationship with immune as well metabolism-related pathways explored. PCD-associated subtypes obtained unsupervised consensus clustering differentially expressed genes analyzed. prognostic signature (PCDRS) constructed best combination 101 machine learning algorithm combinations, C-index PCDRS compared 30 published signatures. In addition, we analyzed relation therapeutic responses. distribution cells explored single-cell analysis spatial transcriptome analysis. Potential drugs targeting key Cmap. Finally, expression clinical tissues verified RT-PCR. showed higher normal. Different groups significant differences pathways. PCDRS, consisting seven genes, robust predictive ability over other signatures datasets. high group had a poorer strongly associated cancer-promoting tumor microenvironment. low exhibited anti-cancer immunity responded better checkpoint inhibitors chemotherapy-related drugs. Clofibrate imatinib could serve potential small-molecule complexes SLC7A5 BCL2A1, respectively. mRNA upregulated tissues. can be used biomarker assess response BRCA patients, which offers novel insights monitoring personalization

Language: Английский

Citations

0