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Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.
This article was published in the following journal.
Name: Cell reports
With 40,920 American women expected to die from breast cancer in 2018 and global health estimates that more than 508,000 women died in 2011 from this disease, the identification of novel therapeutic s...
CDK4/6 pathway is an attractive target for development of anti-cancer drugs. Herein, we reported the design and synthesis of a series of 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives as selec...
Deregulated cell division, resulting in aberrant cell proliferation, is one of the key hallmarks of cancer. Cyclin-dependent kinases (CDKs) play a central role in cell cycle progression in cancer, and...
Cyclin dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) are effective in breast cancer; however, drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 3...
We have recently demonstrated that intratumoral CpG-B vaccination enhances anti-tumor immunity and tumor regression in mice. We further show that the local delivery of TLR9 agonists converts the toler...
This research study is studying a targeted therapy as a possible treatment for cancer abnormality in one of the following genes: CCND1, CCND2, CCND3, CDK4, or CDK6. The drug involved in t...
A Biomarker-driven, Open Label, Single Arm, Multicentre Phase II Study of Abemaciclib in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Who Failed to Platinum-based Therapy
Open, multicenter, single arm, phase II, biomarker driven umbrella trial for head and neck squamous cell carcinoma (FGFR inhibitor, CDK4/6 inhibitor, pan HER inhibitor, PI3K inhibitor, PD1...
In chordoma cell lines and patient biopsies, the p16 (CDKN2A) tumor suppressor is consistently deleted. Thus, chordomas are an example of a tumor with universal activation of the cyclin-de...
Cyclins CDK4 / 6 are extensively involved in the proliferation and growth of numerous cancers including breast cancer. The objective of this study is to identify if a new preoperative oral...
Cyclin D kinase 4 (CDK4) is a key regulator of the G1-S transition in the cell cycle. Alterations in CDK4-cyclin D-retinoblastoma (Rb) pathway may lead to carcinogenesis in many cancers. S...
A B7 antigen subtype that inhibits the costimulation of T-cell activation, proliferation, cytokine production and development of cytotoxicity. The over expression of this protein in a variety of tumor cell types suggests its role in TUMOR IMMUNE EVASION.
Cyclin-dependent kinase 4 is a key regulator of G1 PHASE of the CELL CYCLE. It partners with CYCLIN D to phosphorylate RETINOBLASTOMA PROTEIN. CDK4 activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P16.
Subpopulation of heterogeneous fibroblasts within the TUMOR MICROENVIRONMENT that support NEOPLASTIC CELL TRANSFORMATION and NEOPLASTIC PROCESSES.
A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.
A potent inhibitor of ADENOSINE DEAMINASE. The drug induces APOPTOSIS of LYMPHOCYTES, and is used in the treatment of many lymphoproliferative malignancies, particularly HAIRY CELL LEUKEMIA. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.
Endocrine disorders are grouped into two categories: hormone imbalance - when a gland produces too much or too little of an endocrine hormone development of lesions (such as nodules or tumors) in the endocrine system, which may or may not affect...