A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

Kollmann, Karoline; Heller, Gerwin; Schneckenleithner, Christine; Warsch, Wolfgang; Scheicher, Ruth; Ott, Rene G; Schäfer, Markus; Fajmann, Sabine; Schlederer, Michaela; Schiefer, Ana‐Iris; Reichart, Ursula; Mayerhofer, Matthias; Höeller, Christoph; Zöchbauer‐Müller, Sabine; Kerjaschki, Dontscho; Bock, Christoph; Kenner, Lukas; Höefler, Gerald; Freissmuth, Michael; Green, Andrew; Moriggl, Richard; Busslinger, Meinrad; Malumbres, Marcos; Sexl, Veronika

doi:10.1016/j.ccell.2016.07.003

Cited by 68 publications

(77 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because many of these functions are independent of its interaction with CDK4/6, they would not be expected to be affected by therapeutic inhibition of these CDKs. Moreover, CDK6 has recently been found to have a kinase-independent function in angiogenesis, representing a potentially separate role for CDK6 inhibition in tumor therapy [19].…”

Section: The Cell Cycle and The Balance Between Senescence And Prolifmentioning

confidence: 99%

The Role of CDK4/6 Inhibition in Breast Cancer

2015

View full text Add to dashboard Cite

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptorpositive (ER1) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion.We describe the applicationofsuch therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improvingthe outcomes of patients with ER1 breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting. The Oncologist 2015;20:483-490Implications for Practice: Cyclin-dependent kinases (CDKs) interact with cyclin D proteins to play an integral role in cell cycle progression and represent attractive therapeutic targets in many tumors, including breast cancer. A number of highly selective inhibitors of CDK4 and CDK6 (CDK4/6) are currently in clinical trial development with one agent recently approved by the U.S. Food and Drug Administration for the treatment of advanced ER+, HER2-negative breast cancer.This article reviews the role of CDK4/6 in tumorigenesis and summarizes the clinical trial experience with inhibitors of these kinases in breast cancer. Key efficacy and toxicity data from the clinical trial experience to date have been reviewed. The planned further expansion of their role in breast cancer therapies and potential concerns regarding combinations with other therapies are addressed.

show abstract

Section: The Cell Cycle and The Balance Between Senescence And Prolifmentioning

confidence: 99%

The Role of CDK4/6 Inhibition in Breast Cancer

2015

View full text Add to dashboard Cite

show abstract

“…Cyclin D1/CDK4 complexes phosphorylate methylosome protein 50 leading to protein arginine methyltransferase 5-dependent histone methylation and transcriptional repression of CUL4, which results in overexpression of the replication-licensing protein CDT-1, required for initiation of DNA replication [Aggarwal et al 2010]. Cyclin D-CDK6 complexes, through activation of JUN and signal transducer and activator of transcription 3, induce the expression of p16 INK4A , exerting a negative feedback control of their own activity [Kollmann et al 2013]. Indeed, the transforming effect of CDK6 overexpression may occur only upon deletion or silencing of CDKN2A, the gene encoding p16 INK4A that frequently occurs in breast cancer [Cancer Genome Atlas Network, 2012].…”

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

“…Among these are: a direct role of cyclin D1 in gene transcription [Bienvenu et al 2010]; its involvement in DNA damage repair [Jirawatnotai et al 2011]; its repression of specificity protein 1-mediated transcription [Shao and Robbins, 1995]; inhibition of cyclin D-interacting myb-like protein (DMP1, affecting, via p19 ARF and MDM2, the expression of p53) [Hirai and Sherr, 1996]; induction of vascular endothelial growth factor (VEGF) expression [Yasui et al 2006]; its activating action on the estrogen receptor (ER) [Zwijsen et al 1997], and inhibitory action on the androgen receptor [Reutens et al 2001]. CDK4/6 also regulates the expression of VEGF [Abedin et al 2010;Kollmann et al 2013] and is involved in DNA repair [Dean et al 2012a].…”

Section: Cyclin-dependent Kinases and The Cell Cyclementioning

confidence: 99%

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

et al. 2016

View full text Add to dashboard Cite

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HRpositive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

show abstract

“…63 Forced CDK6 expression in p185 BCR-ABL transformed pro-B cells decreased cell proliferation accompanied by enhanced levels of p16 INK4a , the cell-cycle inhibitor and tumor suppressor, and proangiogenic factor VEGF-A. CDK6 has 2 opposing functions, i.e., the ability to inhibit or accelerate cell proliferation depending on whether p16 INK4a is present or not.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

View full text Add to dashboard Cite

Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

show abstract

A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

Abstract: In the original Figure 3C, the files from patient B were accidentally uploaded twice for patient B and patient C. The corrected files for patient C have been corrected in the figure below. The authors apologize for any confusion this may have caused the readers.

Cited by 68 publications

References 0 publications

The Role of CDK4/6 Inhibition in Breast Cancer

The Role of CDK4/6 Inhibition in Breast Cancer

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

Targeting CDK6 in cancer: State of the art and new insights

Contact Info

Product

Resources

About