The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment

Nature Reviews Clinical Oncology, Год журнала: 2023, Номер 21(2), С. 89 - 105

Опубликована: Дек. 11, 2023

Язык: Английский

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Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer

Breast Cancer Research, Год журнала: 2022, Номер 24(1)

Опубликована: Март 5, 2022

Abstract Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are now an established standard care for patients with advanced hormone receptor-positive breast cancer. The canonical mechanism underlying CDK4/6 inhibitor activity is the suppression phosphorylation retinoblastoma tumor suppressor protein, which serves to prevent cancer cell proliferation. Recent data suggest that these agents induce other diverse effects within both stromal compartments, serve explain aspects their clinical activity. Here, we review phenomena discuss how they might be leveraged in development novel inhibitor-containing combination treatments. We also briefly various known mechanisms acquired resistance setting.

Язык: Английский

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Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

Cell, Год журнала: 2023, Номер 186(12), С. 2628 - 2643.e21

Опубликована: Июнь 1, 2023

Язык: Английский

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Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(49), С. 22622 - 22632

Опубликована: Ноя. 30, 2022

Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not binders. Here, we present a novel approach, termed bridged PROTAC, which utilizes binder of the protein's binding partner to recruit complex into close proximity with an E3 ubiquitin ligase Applying this strategy, discovered MS28, first-in-class degrader cyclin D1, lacks binder. MS28 effectively degrades faster degradation kinetics and superior efficiency than CDK4/6, through recruiting CDK4/6-cyclin D1 von Hippel–Lindau ligase. also suppressed proliferation cancer cells more CDK4/6 inhibitors degraders. Altogether, strategy could provide generalizable platform targeting

Язык: Английский

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Computational analysis of protein-ligand interaction by targeting a cell cycle restrainer

Computer Methods and Programs in Biomedicine, Год журнала: 2023, Номер 231, С. 107367 - 107367

Опубликована: Янв. 24, 2023

Язык: Английский

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Cyclin-dependent protein kinases and cell cycle regulation in biology and disease

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 12, 2025

Abstract Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as kinases able drive division. In reality, human genome contains 20 different CDKs, which can be divided in at least three sub-family with functions, mechanisms regulation, expression patterns and subcellular localization. Most these play fundamental roles normal physiology eucaryotic cells; therefore, their deregulation is associated onset and/or progression multiple disease including but not limited neoplastic neurodegenerative conditions. Here, we describe functions categorized into main functional groups they classified, highlighting most relevant pathways that functions. We then discuss potential CDKs pathologies, a particular focus on cancer, have extensively studied explored therapeutic targets. Finally, how inhibitors become standard therapies selected cancers propose novel ways investigation export targeting from cancer other chronic diseases. hope effort made collecting all available information both prominent lesser-known CDK family members will help identify develop areas research improve lives patients affected by debilitating

Язык: Английский

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Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Chemical Science, Год журнала: 2020, Номер 11(13), С. 3474 - 3486

Опубликована: Янв. 1, 2020

Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein.

Язык: Английский

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Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy

Molecular Therapy, Год журнала: 2021, Номер 29(3), С. 908 - 919

Опубликована: Янв. 1, 2021

A growing amount of evidence suggests that ubiquitination and deubiquitination programmed death 1 (PD-1)/programmed death-ligand (PD-L1) play crucial roles in the regulation PD-1 PD-L1 protein stabilization dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway modulates immune escape cancer patients, its engagement inhibition has significantly reshaped landscape tumor clearance. The abnormal influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe ubiquitination- deubiquitination-mediated modulation signaling through variety E3 ligases deubiquitinating enzymes (DUBs). Moreover, briefly expound on anticancer potential some agents target related ligases, which further modulate cancers. Therefore, review reveals development highly promising therapeutic approach for immunotherapy by targeting ubiquitination.

Язык: Английский

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Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation

eLife, Год журнала: 2020, Номер 9

Опубликована: Апрель 7, 2020

Mammalian cells typically start the cell-cycle entry program by activating cyclin-dependent protein kinase 4/6 (CDK4/6). CDK4/6 activity is clinically relevant as mutations, deletions, and amplifications that increase contribute to progression of many cancers. However, when activated relative CDK2 remained incompletely understood. Here, we developed a reporter system simultaneously monitor activities in single found increases rapidly before gradually increases, can be active after mitosis or inactive for variable time periods. Markedly, stress signals G1 inactivate return quiescence but with reduced probability approach S phase. Together, our study reveals regulation length temporary inactivation mitosis, progressively increasing persistence restricts from returning

Язык: Английский

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Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июнь 7, 2021

Abstract Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite importance, little is known about how affect the stability complexes, which bind cyclins inhibitory proteins such p21. We develop an assay monitor CDK complex inside nucleus. Unexpectedly, treatment with inhibitors—palbociclib, ribociclib, or abemaciclib—immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition CDK2 activity by p27 redistribution. Our work shows that two roles: non-catalytic via displacement catalytic independent By broadening containing next-generation may improved efficacy overcome resistance mechanisms.

Язык: Английский

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