Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A Review of Preclinical and Clinical Data

Vidula, Neelima; Rugo, Hope S.

doi:10.1016/j.clbc.2015.07.005

Cited by 79 publications

(76 citation statements)

References 46 publications

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“…2E). To further probe the effect of CDK inhibition on the survival of MLL-AF9;NRAS G12D cells, we tested the effect of flavopiridol, a small-molecule inhibitor of CDKs 1, 2, 4, 6, 7, 9, and 12 (33,34) and the more selective CDK 4/6 inhibitor palbociclib (35). As shown in Fig.…”

Section: Panobinostat and Dinaciclib Induce Death Of Mll-af9 Tumor Cementioning

confidence: 99%

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

et al. 2016

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Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclibinduced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins. Cancer Res; 76(5); 1158-69. Ó2015 AACR.

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Section: Panobinostat and Dinaciclib Induce Death Of Mll-af9 Tumor Cementioning

confidence: 99%

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

et al. 2016

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“…The cdks drive cell-cycle progression and control transcriptional processes 24,25 . The dysregulation of multiple cdk family members commonly occurs in human cancer.…”

Section: Cdk 4/6 Inhibitors Plus Endocrine Therapymentioning

confidence: 99%

“…The dysregulation of multiple cdk family members commonly occurs in human cancer. The cyclin D-cdk4/6-retinoblastoma protein-ink4 axis is particularly disrupted, facilitating cancer cell proliferation, thus leading to research targeting cdk 4/6 as a therapeutic approach 24,25 . Palbociclib was the first oral small-molecule cdk 4/6 inhibitor to be developed.…”

Section: Cdk 4/6 Inhibitors Plus Endocrine Therapymentioning

confidence: 99%

Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer: Redrawing the Lines

et al. 2018

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Estrogen receptor modulators and estrogen deprivation have become standards of care for hormone receptorpositive metastatic breast cancer. However, after traditional first-line endocrine monotherapy treatment, the disease typically progresses despite the initial high rate of clinical benefit. Multiple studies have aimed at optimizing treatment strategies to improve upon clinical benefit beyond the traditional single-agent endocrine treatment. With the availability of new data and novel therapies, the clinical practice challenge becomes how best to define the optimal treatment sequence to maximize clinical benefit. In this review, we present treatment options clinically relevant to the management of hormone-positive, her2-negative metastatic breast cancer, and we propose a treatment algorithm based on the current literature.

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“…Currently, high specific CDK4/6 inhibitors show a selective and potent therapeutic effect and fewer off-target toxicities than pan-CDK inhibitors for the treatment of breast cancer [14,15]. There are three CDK4/6 inhibitors which deactivate these CDK at <40 nM IC50 values: palbociclib, ribociclib and abemaciclib [16].…”

Section: Palbociclib Is the First Cell Cycle Inhibitor On Demonstratementioning

confidence: 99%

“…The striking clinical activity exhibited by palbociclib in breast cancer announces its additional role in other cancer types. Clinical trials are on the way to explore the synergist effects of CDK4/6 inhibitors and drugs of other classes, such as other hormonal therapies, PI3K/AKT/mTOR pathway inhibitors and RAS/RAF/MEK/ERK pathways inhibitors [11,14,16]. The development and the flourishing of clinical results of the CDK4/6 inhibitors has changed the perception of CDKs as therapeutic targets in cancer.…”

Section: Palbociclib Is the First Cell Cycle Inhibitor On Demonstratementioning

confidence: 99%

Increasing the Potential Targets and Molecularly Targeted Agent Combinations Against Cancer Cell Proliferation

Valdespino¹,

Valdespino-Castillo²,

Valdespino-Castillo³

2017

J Cell Signal

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At least four main groups of intracellular signaling pathways or submodules concur in the cell division and proliferation module: those for the control of the cell cycle, those for the metabolism programming, those for cytoskeleton remodeling, and those for DNA replication and repair. Precise signaling pathways that control cell proliferation module require the joint functional collaboration of signaling pathways of cell growth, cell survival, cell differentiation, intracellular senescence and death programs, and appropriate interaction with angiogenesis, cell micro-environment regulation and immunologic system modules. Seeking out actionable aberrations in cancer cells may now selectively targeted by drug compounds to optimize treatment efficacy and minimize toxicity.This critical review provides an overview of the use of the CDK4/6 inhibitors as the first cell cycle inhibitor that improve the outcomes of patients with HR+ breast cancer. Discusses the connection of different inhibitory agents to modify cell proliferation signaling pathways and sketches the potential use of other molecularly targeted agents in close relationship with proliferation signaling pathways carcinoma cells.

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Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A Review of Preclinical and Clinical Data

Cited by 79 publications

References 46 publications

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer: Redrawing the Lines

Increasing the Potential Targets and Molecularly Targeted Agent Combinations Against Cancer Cell Proliferation

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