A landscape of response to drug combinations in non-small cell lung cancer DOI Creative Commons
Nishanth Ulhas Nair,

Patricia Greninger,

Xiaohu Zhang

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 28, 2023

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy single agents. The design and testing combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent across 81 non-small cell lung cancer lines. Our analysis reveals profound heterogeneity response tumor models. Notably, rarely result in strong gain range observable with Importantly, activity agents more often when co-targeting functionally proximal genes, offering strategy for designing efficient combinations. Because combinatorial effect strongly context specific, specificity should be achievable. resource provided, together an additional validation screen sheds light on major challenges opportunities building efficacious against provides opportunity training computational models synergy prediction.

Language: Английский

The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment DOI
Laura Morrison, Sibylle Loibl, Nicholas C. Turner

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 21(2), P. 89 - 105

Published: Dec. 11, 2023

Language: Английский

Citations

109
Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer DOI Creative Commons
April C. Watt, Shom Goel

Breast Cancer Research, Journal Year: 2022, Volume and Issue: 24(1)

Published: March 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.

Language: Английский

Citations

87
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
Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets DOI
Yan Xiong, Yue Zhong, Hyerin Yim

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(49), P. 22622 - 22632

Published: Nov. 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

Language: Английский

Citations

70
Computational analysis of protein-ligand interaction by targeting a cell cycle restrainer DOI
Rahul Singh, Rituraj Purohit

Computer Methods and Programs in Biomedicine, Journal Year: 2023, Volume and Issue: 231, P. 107367 - 107367

Published: Jan. 24, 2023

Language: Английский

Citations

54
Cyclin-dependent protein kinases and cell cycle regulation in biology and disease DOI Creative Commons
Ilenia Pellarin, Alessandra Dall’Acqua, Andrea Favero

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 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

Language: Английский

Citations

12
Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders DOI Creative Commons
Christian Steinebach, Yuen Lam Dora Ng, Izidor Sosič

et al.

Chemical Science, Journal Year: 2020, Volume and Issue: 11(13), P. 3474 - 3486

Published: Jan. 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.

Language: Английский

Citations

106
Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy DOI Creative Commons
Xiaoli Hu, Jing Wang,

Man Chu

et al.

Molecular Therapy, Journal Year: 2021, Volume and Issue: 29(3), P. 908 - 919

Published: Jan. 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.

Language: Английский

Citations

98
Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation DOI Creative Commons
Hee Won Yang, Steven D. Cappell,

Ariel Jaimovich

et al.

eLife, Journal Year: 2020, Volume and Issue: 9

Published: April 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

Language: Английский

Citations

78
Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2 DOI Creative Commons
Lindsey R. Pack, Leighton H. Daigh, Mingyu Chung

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 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.

Language: Английский

Citations

77