&lt;p&gt;Current Therapeutic Progress of CDK4/6 Inhibitors in Breast Cancer&lt;/p&gt;

Wu, Yanmei; Pi, Hao; Yuan, Shengtao

doi:10.2147/cmar.s250632

Cited by 41 publications

(30 citation statements)

References 92 publications

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“…One class of targeted therapeutics that may benefit from the modification of senescence is the CDK4/6 inhibitors (CDK4/6i). Specifically, three CDK4/6i, including Palbociclib, Ribociclib, and Abemaciclib, have been approved for the treatment of patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer and are under evaluation in clinical trials for other cancers such as melanoma [13][14][15][16]. Further, the CDK4/6i Palbociclib has been shown to induce senescence in a variety of cancer cell lines that express functional retinoblastoma protein (pRB) as well as in solid tumors in vivo [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma

Bayer

Pietruska

Farrell

et al. 2022

Cancers

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Cellular senescence is a carefully regulated process of proliferative arrest accompanied by functional and morphologic changes. Senescence allows damaged cells to avoid neoplastic proliferation; however, the induction of the senescence-associated secretory phenotype (SASP) can promote tumor growth. The complexity of senescence may limit the efficacy of anti-neoplastic agents, such as CDK4/6 inhibitors (Cdk4/6i), that induce a senescence-like state in tumor cells. The AKT kinase family, which contains three isoforms that play both unique and redundant roles in cancer progression, is commonly hyperactive in many cancers including melanoma and has been implicated in the regulation of senescence. To interrogate the role of AKT isoforms in Cdk4/6i-induced cellular senescence, we generated isoform-specific AKT knockout human melanoma cell lines. We found that the CDK4/6i Palbociclib induced a form of senescence in these cells that was dependent on AKT1. We then evaluated the activity of the cGAS-STING pathway, recently implicated in cellular senescence, finding that cGAS-STING function was dependent on AKT1, and pharmacologic inhibition of cGAS had little effect on senescence. However, we found SASP factors to require NF-κB function, in part dependent on a stimulatory phosphorylation of IKKα by AKT1. In summary, we provide the first evidence of a novel, isoform-specific role for AKT1 in therapy-induced senescence in human melanoma cells acting through NF-κB but independent of cGAS.

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Section: Introductionmentioning

confidence: 99%

AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma

Bayer

Pietruska

Farrell

et al. 2022

Cancers

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“…CDKN2C interacts with cyclin-dependent kinases 4 and 6 (CDK4/6) and prevents their activation (115,116). Three CDK4/6 inhibitors have been approved for treatment of hormone receptor+/HER2+ breast cancer: palbociclib, ribociclib and abemaciclib (117,118). Ongoing clinical studies in other types of solid tumors including ESCC have been reported (119).…”

Section: Lncrna Linp1 Induces Epithelial-mesenchymal Transitionmentioning

confidence: 99%

Long Non-coding RNAs WithIn VitroandIn VivoEfficacy in Preclinical Models of Esophageal Squamous Cell Carcinoma Which Act by a Non-microRNA Sponging Mechanism

Weidle

Birzele

2022

Cancer Genomics Proteomics

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“…The pan‐CDK inhibitor roscovitine is in phase II clinical trial for colitis and cystic fibrosis, both neutrophil‐mediated diseases 13 . CDK4/6 inhibitors, such as palbociclib, ribocilcib, and abemaciclib, are approved to treat metastatic breast cancer 14,15 . Since neutrophils also play a prominent role in the progression of cancer, 16 it is possible that neutrophil suppression contributed to the therapeutic outcome.…”

Section: Introductionmentioning

confidence: 99%

A curious case of cyclin-dependent kinases in neutrophils

Syahirah

Hsu

Deng

2022

Journal of Leukocyte Biology

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Neutrophils are terminally differentiated, short‐lived white blood cells critical for innate immunity. Although cyclin‐dependent kinases (CDKs) are typically related to cell cycle progression, increasing evidence has shown that they regulate essential functions of neutrophils. This review highlights the roles of CDKs and their partners, cyclins, in neutrophils, outside of cell cycle regulation. CDK1‐10 and several cyclins are expressed in neutrophils, albeit at different levels. Observed phenotypes associated with specific inhibition or genetic loss of CDK2 indicate its role in modulating neutrophil migration. CDK4 and 6 regulate neutrophil extracellular traps (NETs) formation, while CDK5 regulates neutrophil degranulation. CDK7 and 9 are critical in neutrophil apoptosis, contributing to inflammation resolution. In addition to the CDKs that regulate mature neutrophil functions, cyclins are essential in hematopoiesis and granulopoiesis. The pivotal roles of CDKs in neutrophils present an untapped potential in targeting CDKs for treating neutrophil‐dominant inflammatory diseases and understanding the regulation of the neutrophil life cycle.

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<p>Current Therapeutic Progress of CDK4/6 Inhibitors in Breast Cancer</p>

Cited by 41 publications

References 92 publications

AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma

AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma

Long Non-coding RNAs WithIn VitroandIn VivoEfficacy in Preclinical Models of Esophageal Squamous Cell Carcinoma Which Act by a Non-microRNA Sponging Mechanism

A curious case of cyclin-dependent kinases in neutrophils

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