Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer

Palumbo, A; Lau, G.; Saraceni, Megan M.

doi:10.1177/1060028018795146

Cited by 30 publications

(31 citation statements)

References 25 publications

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“…The Food and Drug Administration (FDA) has approved the CDK4/6 inhibitors Palbociclib, Ribociclib and Abemaciclib for treating metastatic breast cancer. These inhibitors have also demonstrated promising antitumor potentials both as a monotherapy and in combined therapy in numerous clinical trials [3–6]. CDK11 is a member of the serine/threonine protein kinase family.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

et al. 2019

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Background Aberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer. CDK11 plays a crucial role in cancer cell growth and proliferation. However, the molecular mechanisms of CDK11 and CDK11 transcriptionally regulated genes are largely unknown. Methods In this study, we performed a global transcriptional analysis using gene array technology to investigate the transcriptional role of CDK11 in osteosarcoma. The promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay were used to identify direct transcriptional targets of CDK11. Clinical relevance and function of core-binding factor subunit beta (CBFβ) were further accessed in osteosarcoma. Results We identified a transcriptional role of protein-DNA interaction for CDK11p110, but not CDK11p58, in the regulation of CBFβ expression in osteosarcoma cells. The CBFβ promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay confirmed that CBFβ is a direct transcriptional target of CDK11. High expression of CBFβ is associated with poor outcome in osteosarcoma patients. Expression of CBFβ contributes to the proliferation and metastatic behavior of osteosarcoma cells. Conclusions These data establish CBFβ as a mediator of CDK11p110 dependent oncogenesis and suggest that targeting the CDK11- CBFβ pathway may be a promising therapeutic strategy for osteosarcoma treatment. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

et al. 2019

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“…MONARCH 1, 2, and 3 clinical trials established Abemaciclib as an orally effective CDK4/6 inhibitor for HR+/HER2- advanced or metastatic breast cancer 72, 73.…”

Section: Discussionmentioning

confidence: 99%

Latest Overview of the Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: The Past, the Present and the Future

Xiu¹,

Xu²,

Li³

et al. 2019

J. Cancer

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Endocrine resistance in hormone receptor positive breast cancer patients urges us to develop novel approaches such as inhibitors of the cyclin-dependent kinases (CDK) 4/6 to reverse its resistance. Nowadays, three selective CDK4/6 inhibitors (Palbociclib, Ribociclib and Abemaciclib) are approved by Federal Drug Administration and the European Medicines Agency for the treatment of advanced and metastatic HR+/HER2-breast cancer. However, no consistent conclusion has been reached to its application in other types of breast cancer. Therefore, the purpose of our study was to overview the clinical trials about the beneficial effects of Palbociclib, Ribociclib and Abemaciclib in breast cancer with their tolerable adverse effects, and discuss their resistant mechanisms thus looking for useful biomarkers to predict the efficiency of the CDK4/6 inhibitors. The CDK4/6 inhibitors application after the support of preclinic and clinic data will be helpful to provide other alternatively suitable strategies for different types of breast cancer patients.

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“…CDK4 is a key member of the cell cycle-related subfamily,38 and it is reported to be involved in many physiological processes, including proliferation and apoptosis 39,40. In addition, CDK4 has been demonstrated to be regulated by post-translational modification of miR and acts downstream of multiple signaling pathways involved in cell proliferation and movement, and the carcinogenic effects of CDK4 have gradually emerged in some common human cancers, including BC 30,41,42. It was further observed that overexpression of CDK4 impaired the suppressive functions of miR-124 on BC cell viability, angiogenesis and proliferation in T24 cells and 5637 cells.…”

Section: Discussionmentioning

confidence: 99%

<p>The functions of microRNA-124 on bladder cancer</p>

Cao¹,

Xu²,

Zhao³

et al. 2019

OTT

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Background: To detect the expression of miR-124 in bladder cancer (BC) cell lines and tissue specimens and to analyze its association with the growth of the BC cells. Methods: Quantitative real-time polymerase chain reaction (qPCR) was applied to examine the expression of miR-124 in BC cell lines and tissues. The function of miR-124 in modulating cell proliferation was assessed in BC cells with miRNA-124 overexpression; the cell viability was identified by Cell Count Kit-8; flow cytometry was employed to detect the cell cycle; the expressions of E2F3, cyclin-dependent kinase 4 (CDK4), Ki-67 and vascular endothelial growth factor (VEGF) were tested by qPCR and Western blot; angiogenesis experiment was performed to analysis changes in angiogenesis rate; and bioinformatics prediction and dual luciferase reporter system were employed to identify the target of miR-124. Results: Survival curve data showed that the expression of MicroRNA-124 was positively correlated with survival. MicroRNA-124 expression was significantly decreased in BC cell lines and tissues. Bioinformatics prediction and dual luciferase reporter system verified CDK4 as a direct target of miR-124, which regulated the proliferation of BC cells by directly inhibiting CDK4. BC cells over-expressing miR-124 showed significantly inhibited cell viability, decreased angiogenesis rate, prevented cell proliferation and diminished the expression of E2F3, CDK4, Ki-67 and VEGF. All of these changes were reversed by over-expressing CDK4. Conclusion: MicroRNA-124 suppressed the proliferation of CRC cells by directly targeting CDK4, which provides a target for improving the therapeutic effect of BC.

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Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer

Abstract: Abemaciclib is an effective and well-tolerated treatment for HR-positive, HER2-negative advanced or metastatic breast cancer.

Cited by 30 publications

References 25 publications

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

Latest Overview of the Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: The Past, the Present and the Future

<p>The functions of microRNA-124 on bladder cancer</p>

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