Cell cycle machinery in oncology: A comprehensive review of therapeutic targets DOI Creative Commons
Simona Cavalu, A. M. Abdelhamid, Sameh Saber

et al.

The FASEB Journal, Journal Year: 2024, Volume and Issue: 38(11)

Published: June 7, 2024

The cell cycle is tightly regulated to ensure controlled proliferation. Dysregulation of the machinery a hallmark cancer that leads unchecked growth. This review comprehensively analyzes key molecular regulators and how they contribute carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, mitotic as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, abemaciclib for breast treatment. Other possible targets anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus combinatorial therapies, next-generation biomarkers patient selection. Targeting holds promise but further optimization necessary fully exploit it an anti-cancer strategy across diverse malignancies.

Language: Английский

p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition DOI Open Access
Keelan Z. Guiley, Jack W. Stevenson, Kevin Lou

et al.

Science, Journal Year: 2019, Volume and Issue: 366(6471)

Published: Dec. 13, 2019

The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated tyrosine kinases, allosterically activated CDK4 in complex cyclin D1 (CDK4-CycD1). Structural biochemical data revealed binding (phosp27) to altered the kinase adenosine triphosphate site promote phosphorylation retinoblastoma tumor suppressor (Rb) other substrates. Surprisingly, purified endogenous phosp27-CDK4-CycD1 complexes were insensitive CDK4-targeting drug palbociclib. Palbociclib instead targeted monomeric CDK6 (CDK4/6) breast cells. Our characterize as an Rb refractory clinically relevant CDK4/6 inhibitors.

Language: Английский

Citations

188
Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019) DOI
Concepción Sánchez‐Martínez, Marı́a José Lallena,

Sonia Gutiérrez Sanfeliciano

et al.

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2019, Volume and Issue: 29(20), P. 126637 - 126637

Published: Aug. 26, 2019

Language: Английский

Citations

178
A unified model for the G1/S cell cycle transition DOI Creative Commons
Samuel Hume, Grigory L. Dianov, Kristijan Ramadan

et al.

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(22), P. 12483 - 12501

Published: Oct. 14, 2020

Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited causes replication stress, DNA damage oncogenesis, highlighting the need strict regulation. Recent paradigm shifts conflicting reports demonstrate requirement a discussion of G1/S transition literature. Here, we review recent studies, propose unified model decision. In this model, competition between mitogen signalling over course mother cell cycle constitutes predominant control mechanism daughter cells. Mitogens have distinct sensing periods, giving rise to three Commitment Points (CP1-3). mitogen-independent in G1 phase, but remains sensitive damage, such as single strand breaks, most frequently-occurring lesions that uniquely threaten replication. To CP1-3, dedicated hubs integrate antagonistic mitogenic signals, regulating stoichiometric cyclin: CDK inhibitor ratio ultrasensitive CDK4/6 CDK2. This combines findings decades study, provides an updated foundation research.

Language: Английский

Citations

144
Structure of the human Mediator–RNA polymerase II pre-initiation complex DOI
Srinivasan Rengachari, S. Schilbach, Shintaro Aibara

et al.

Nature, Journal Year: 2021, Volume and Issue: 594(7861), P. 129 - 133

Published: April 26, 2021

Language: Английский

Citations

105
Ligand binding remodels protein side-chain conformational heterogeneity DOI Creative Commons
Stephanie A. Wankowicz,

Saulo H de Oliveira,

Daniel W. Hogan

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: March 21, 2022

While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions heterogeneity. Here, through multiconformer modeling time- space-averaged electron density, we measure 743 stringently matched pairs crystallographic datasets that reflect unbound/apo ligand-bound/holo states. When comparing side chains, observe when binding site residues become more rigid upon distant tend flexible, especially non-solvent-exposed regions. Among properties, increased flexibility as number hydrogen bonds decreases relative hydrophobicity increases. Across series 13 inhibitor-bound structures CDK2, find correlated inhibitor features identify how changes propagate differences away from site. Collectively, our findings agree models emerging nuclear magnetic resonance studies suggesting residual side-chain entropy modulate affinity point need integrate binding.

Language: Английский

Citations

73
Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity DOI Creative Commons
Mansi Arora, Justin Moser, Timothy E. Hoffman

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(12), P. 2628 - 2643.e21

Published: June 1, 2023

Language: Английский

Citations

72
Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer DOI
Jennifer E. Klomp, J. Nathaniel Diehl, Jeffrey A. Klomp

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6700)

Published: June 6, 2024

To delineate the mechanisms by which ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We that share near-identical signaling transforming outputs KRAS-regulated is driven nearly completely ERK. identified 4666 phosphosites on 2123 proteins, of 79 66%, respectively, were not previously associated with ERK, substantially expanding depth breadth phosphorylation events revealing a considerably more complex function for ERK established controls highly dynamic converges cyclin-dependent kinase regulation RAS homolog guanosine triphosphatase (RHO GTPase). Our findings establish most comprehensive molecular portrait drives KRAS-dependent growth.

Language: Английский

Citations

21
The application and prospect of CDK4/6 inhibitors in malignant solid tumors DOI Creative Commons

Qi Du,

Xiang Guo, Miao Wang

et al.

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: May 1, 2020

Abstract Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which block the transition from G1 to S phase of cell cycle by interfering with Rb phosphorylation and E2F release, have shown potent antitumor activity manageable toxicity in HR+/HER2− breast cancer patients. Some clinical trials involving CDK4/6 inhibitors other tumors achieved preliminary impressive efficacy. Whether possess great potential as broad-spectrum drugs how maximize their benefits remain uncertain. TCGA database analysis showed that genes related are widely expressed among various tumors, high or moderate expression commonly indicates poor survival. gene is significantly higher COAD, ESCA, STAD, LIHC, HNSC, suggesting could be more efficacious those tumors. Moreover, network STRING demonstrated CDK4/6-related proteins were co-expressed co-occurred classical tumor signaling pathways, such pathway, RAS PI3K Myc p53 pathway. The extensive effects may synergizing antagonizing molecule combination therapy might most effective treatment strategy. This article analyzed feasibility expanding application at genetic level further summarized associated clinical/preclinical studies collect supportive evidence. first study presents a theoretical foundation for inhibitor precision via combined comprehensive information research results.

Language: Английский

Citations

123
Development of selective mono or dual PROTAC degrader probe of CDK isoforms DOI
Fei Zhou,

Luyu Chen,

Chao-Guo Cao

et al.

European Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 187, P. 111952 - 111952

Published: Dec. 5, 2019

Language: Английский

Citations

92
Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact DOI Creative Commons

Armando Arroyo,

Beomsu Kim,

John Yeh

et al.

Reproductive Sciences, Journal Year: 2020, Volume and Issue: 27(6), P. 1223 - 1252

Published: Jan. 6, 2020

Abstract The ovarian follicle luteinizing hormone (LH) signaling molecules that regulate oocyte meiotic maturation have recently been identified. LH signal reduces preovulatory cyclic nucleotide levels which releases oocytes from the first arrest. In follicle, via CNP/NPR2 system, EGF/EGF receptor network, and follicle/oocyte gap junctions. oocyte, reduced activate promoting factor (MPF). activated MPF induces chromosome segregation completion of second divisions. purpose this paper is to present an overview current understanding human regulation by identifying integrating studies on topic. We found 89 in literature identified 24 proteins. These show regulated same proteins animal maturation. also these pathway quality subsequent embryo quality. Remarkably, vitro (IVM) prematuration culture (PMC) protocols manipulate improve cultured oocytes. This knowledge has improved clinical IVM efficiency may become a routine alternative ART for some infertile patients.

Language: Английский

Citations

86