The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer DOI Open Access
Lei Ding,

Jiaqi Cao,

Wen-Shan Lin

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(6), P. 1960 - 1960

Published: March 13, 2020

Cyclin-dependent kinases (CDKs) are serine/threonine whose catalytic activities regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints transcriptional events response to extracellular intracellular signals. Not surprisingly, the dysregulation of is a hallmark cancers, inhibition specific members considered an attractive target cancer therapy. In breast (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, combined other agents, were approved Food Drug Administration (FDA) recently for treatment hormone receptor positive (HR+) advanced or metastatic (A/MBC), as well sub-types cancer. Furthermore, ongoing studies identified more selective promising clinical targets. this review, we focus on roles driving progression, checkpoints, regulation, highlight dysregulated activation BC. We also discuss most relevant currently BC trials, special emphasis used estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, emerging precise therapeutic strategies, such combination therapies microRNA (miRNA)

Language: Английский

Palbociclib and Letrozole in Advanced Breast Cancer DOI Open Access
Richard S. Finn, Miguel Martín, Hope S. Rugo

et al.

New England Journal of Medicine, Journal Year: 2016, Volume and Issue: 375(20), P. 1925 - 1936

Published: Nov. 16, 2016

A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than alone in the initial treatment of postmenopausal women estrogen-receptor (ER)–positive, human epidermal growth factor receptor (HER2)–negative advanced breast cancer. We performed a 3 designed to confirm and expand efficacy safety data for this indication.

Language: Английский

Citations

2426
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay DOI

Daniel Martinez Molina,

Rozbeh Jafari,

Marina Ignatushchenko

et al.

Science, Journal Year: 2013, Volume and Issue: 341(6141), P. 84 - 87

Published: July 4, 2013

The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization target engagement by drugs in cells often challenging, because cannot be monitored inside cells. We have developed method for evaluating proteins and tissue samples. This cellular thermal shift assay (CETSA) based the biophysical principle ligand-induced stabilization proteins. Using this assay, we validated set important clinical targets processes transport activation, off-target effects resistance cancer cell lines, as well distribution tissues. CETSA likely become valuable tool validation optimization engagement.

Language: Английский

Citations

1821
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study DOI
Richard S. Finn, John Crown,

István Láng

et al.

The Lancet Oncology, Journal Year: 2014, Volume and Issue: 16(1), P. 25 - 35

Published: Dec. 16, 2014

Language: Английский

Citations

1745
Cell cycle proteins as promising targets in cancer therapy DOI
Tobias Otto, Piotr Siciński

Nature reviews. Cancer, Journal Year: 2017, Volume and Issue: 17(2), P. 93 - 115

Published: Jan. 27, 2017

Language: Английский

Citations

1672
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways DOI Open Access
Ping Wee, Zhixiang Wang

Cancers, Journal Year: 2017, Volume and Issue: 9(5), P. 52 - 52

Published: May 17, 2017

The epidermal growth factor receptor (EGFR) is a tyrosine kinase that commonly upregulated in cancers such as non-small-cell lung cancer, metastatic colorectal glioblastoma, head and neck pancreatic breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations truncations to its extracellular domain, EGFRvIII truncations, well L858R T790M mutations, or exon 19 truncation. These aberrations over-activate downstream pro-oncogenic signaling pathways, RAS-RAF-MEK-ERK MAPK AKT-PI3K-mTOR pathways. pathways then activate many biological outputs are beneficial cancer cell proliferation, their chronic initiation progression through cycle. Here, we review molecular regulate signal transduction, structure ligand binding dimerization, lead G1 cycle progression. We focus on induction CYCLIN D expression, CDK4/6 activation, repression cyclin-dependent inhibitor proteins (CDKi) by also discuss successes challenges EGFR-targeted therapies, potential for use combination with inhibitors.

Language: Английский

Citations

1589
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial DOI Creative Commons
Massimo Cristofanilli, Nicholas C. Turner, Igor Bondarenko

et al.

The Lancet Oncology, Journal Year: 2016, Volume and Issue: 17(4), P. 425 - 439

Published: March 3, 2016

Language: Английский

Citations

1581
The history and future of targeting cyclin-dependent kinases in cancer therapy DOI
Uzma Asghar, Agnieszka K. Witkiewicz, Nicholas C. Turner

et al.

Nature Reviews Drug Discovery, Journal Year: 2015, Volume and Issue: 14(2), P. 130 - 146

Published: Jan. 30, 2015

Language: Английский

Citations

1570
Melanoma biology and new targeted therapy DOI

Vanessa C. Gray‐Schopfer,

Claudia Wellbrock, Richard Marais

et al.

Nature, Journal Year: 2007, Volume and Issue: 445(7130), P. 851 - 857

Published: Feb. 21, 2007

Language: Английский

Citations

1316
PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro DOI Creative Commons
Richard S. Finn,

Judy Dering,

Dylan Conklin

et al.

Breast Cancer Research, Journal Year: 2009, Volume and Issue: 11(5)

Published: Oct. 29, 2009

Alterations in cell cycle regulators have been implicated human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation low nanomolar range. To identify predictors response, we determined vitro sensitivity across a panel molecularly characterized cancer lines.Forty-seven immortalized lines representing known molecular subgroups were treated determine IC50 values. These data analyzed against baseline gene expression genes associated response.Cell luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) most sensitive growth inhibition by while nonluminal/basal subtypes resistant. Analysis variance identified 450 differentially expressed between resistant cells. pRb D1 elevated CDKN2A (p16) was decreased lines. Cell analysis showed G0/G1 arrest Western blot demonstrated Rb blocked but not synergistic tamoxifen trastuzumab ER+ HER2-amplified lines, respectively. enhanced conditioned resistance ER blockade.These studies suggest role for CDK4/6 some cancers criteria patient selection clinical

Language: Английский

Citations

1291
Cyclin D as a therapeutic target in cancer DOI

Elizabeth A. Musgrove,

C. Elizabeth Caldon,

Jane Barraclough

et al.

Nature reviews. Cancer, Journal Year: 2011, Volume and Issue: 11(8), P. 558 - 572

Published: July 7, 2011

Language: Английский

Citations

1279