The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies

Molecular portraits of human breast tumours

2000 • 15,445 citations

Evaluation of Factors Related to Late Recurrence - Later than 10 Years after the Initial Treatment - in Primary Breast Cancer

2013 • 12,861 citations

Cancer Cell Cycles

1996 • 5,379 citations

Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a

1997 • 4,870 citations

Ki67 expression in breast cancer

2016 • 4,269 citations

A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4

1993 • 3,680 citations

Integrative Clinical Genomics of Advanced Prostate Cancer

2015 • 3,212 citations

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

2005 • 2,633 citations

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

2011 • 2,616 citations

Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization

1998 • 2,096 citations

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

2006 • 1,867 citations

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

2014 • 1,707 citations

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer

2016 • 1,609 citations

The history and future of targeting cyclin-dependent kinases in cancer therapy

2015 • 1,510 citations

Senescence in premalignant tumours

2005 • 1,394 citations

Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer

2015 • 1,341 citations

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

2009 • 1,268 citations

Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

2010 • 1,218 citations

Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts

2004 • 1,165 citations

Mechanisms of Endocrine Resistance in Breast Cancer

2010 • 1,087 citations

Functional Inactivation of the Retinoblastoma Protein Requires Sequential Modification by at Least Two Distinct Cyclin-cdk Complexes

1998 • 1,058 citations

Living with or without cyclins and cyclin-dependent kinases

2004 • 1,047 citations

Regulation of retinoblastoma protein functions by ectopic expression of human cyclins

1992 • 1,031 citations

Cyclin D1 provides a link between development and oncogenesis in the retina and breast

1995 • 1,017 citations

D-type cyclins

1995 • 978 citations

Treating cancer with selective CDK4/6 inhibitors

2016 • 932 citations

Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins

1992 • 906 citations

Forging a signature of in vivo senescence

2015 • 905 citations

Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16

1995 • 894 citations

Targeting CDK4 and CDK6: From Discovery to Therapy

2015 • 805 citations

Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway.

1997 • 747 citations

Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis

1996 • 700 citations

Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia

1999 • 693 citations

Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer

2016 • 658 citations

Exit from G1 and S Phase of the Cell Cycle Is Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF

2000 • 650 citations

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

2016 • 625 citations

Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer

2016 • 607 citations

Role for E2F in Control of Both DNA Replication and Mitotic Functions as Revealed from DNA Microarray Analysis

2001 • 587 citations

Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation.

1993 • 514 citations

Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine

2014 • 508 citations

Cycling to Cancer with Cyclin D1

2002 • 462 citations

Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype

2011 • 445 citations

Estrogen-induced Activation of Cdk4 and Cdk2 during G1-S Phase Progression Is Accompanied by Increased Cyclin D1 Expression and Decreased Cyclin-dependent Kinase Inhibitor Association with Cyclin E-Cdk2

1997 • 438 citations

Putting the stress on senescence

2001 • 407 citations

CDK 4/6 Inhibitors Sensitize PIK3CA Mutant Breast Cancer to PI3K Inhibitors

2014 • 405 citations

Cyclin D activates the Rb tumor suppressor by mono-phosphorylation

2014 • 401 citations

A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma

2010 • 398 citations

Inhibition of Ras-Induced Proliferation and Cellular Transformation by p16 ^INK4

1995 • 382 citations

Cyclin E-induced S phase without activation of the pRb/E2F pathway.

1997 • 381 citations

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

2010 • 375 citations

Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With AdvancedCDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma

2013 • 372 citations

Cyclin D1 Is Dispensable for G₁ Control in Retinoblastoma Gene-Deficient Cells Independently of cdk4 Activity

1995 • 370 citations

Cyclin D1: polymorphism, aberrant splicing and cancer risk

2006 • 360 citations

Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma

2012 • 355 citations

Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma

2013 • 350 citations

Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

2016 • 346 citations

Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence

2016 • 343 citations

Phase I, Dose-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, Administered Using a 21-Day Schedule in Patients with Advanced Cancer

2011 • 341 citations

Emerging roles for E2F: Beyond the G1/S transition and DNA replication

2003 • 334 citations

The Requirement for Cyclin D Function in Tumor Maintenance

2012 • 311 citations

Differential Regulation of Retinoblastoma Protein Function by Specific Cdk Phosphorylation Sites

1996 • 306 citations

Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response.

2003 • 304 citations

ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer

2011 • 301 citations

Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.

1993 • 295 citations

Induction of cyclin D1 overexpression by activated ras.

1994 • 295 citations

Dual Mechanisms for the Inhibition of E2F Binding to RB by Cyclin-Dependent Kinase-Mediated RB Phosphorylation

1997 • 293 citations

Pharmacologic Inhibition of Cyclin-Dependent Kinases 4 and 6 Arrests the Growth of Glioblastoma Multiforme Intracranial Xenografts

2010 • 289 citations

A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas

2016 • 281 citations

Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma

2012 • 279 citations

Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer

2011 • 277 citations

Expression of p16 and Retinoblastoma Determines Response to CDK4/6 Inhibition in Ovarian Cancer

2011 • 275 citations

Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy

1996 • 264 citations

c-Myc or Cyclin D1 Mimics Estrogen Effects on Cyclin E-Cdk2 Activation and Cell Cycle Reentry

1998 • 257 citations

Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

2014 • 254 citations

Cyclins and Breast Cancer

2004 • 251 citations

The meaning of p16^ink4aexpression in tumors

2011 • 249 citations

Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1)

2011 • 244 citations

Deciphering the retinoblastoma protein phosphorylation code

2012 • 237 citations

Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy

2012 • 233 citations

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

2014 • 232 citations

Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM

2010 • 218 citations

Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors

2012 • 212 citations

Inhibition of DNA synthesis by RB: effects on G₁/S transition and S-phase progression

1998 • 209 citations

Lifetime Risk of Melanoma in CDKN2A Mutation Carriers in a Population-Based Sample

2005 • 206 citations

CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer

2014 • 201 citations

Loss of <scp>CDKN</scp>2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the <scp>CDK</scp>4/6 inhibitor <scp>PD</scp>0332991 in melanoma cell lines

2014 • 179 citations

Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities

2016 • 176 citations

p16Ink4a in Melanocyte Senescence and Differentiation

2002 • 174 citations

Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia

2012 • 172 citations

An integrated view of cyclin E function and regulation

2012 • 159 citations

Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity

2006 • 146 citations

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy–Resistant Breast Cancer

2015 • 142 citations

Cyclin E2 Overexpression Is Associated with Endocrine Resistance but not Insensitivity to CDK2 Inhibition in Human Breast Cancer Cells

2012 • 140 citations

PD-0332991, a CDK4/6 Inhibitor, Significantly Prolongs Survival in a Genetically Engineered Mouse Model of Brainstem Glioma

2013 • 139 citations

Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6

2016 • 139 citations

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

2015 • 137 citations

Abstract S1-6: Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (BC)

2012 • 129 citations

Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia

2007 • 126 citations

MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition

2015 • 125 citations

Proliferative Suppression by CDK4/6 Inhibition: Complex Function of the Retinoblastoma Pathway in Liver Tissue and Hepatoma Cells

2010 • 122 citations

Unbiased analysis of RB-mediated transcriptional repression identifies novel targets and distinctions from E2F action.

2002 • 119 citations

Cdk4/6 Inhibition Induces Epithelial–Mesenchymal Transition and Enhances Invasiveness in Pancreatic Cancer Cells

2012 • 119 citations

Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

2016 • 116 citations

Deregulated Cyclin D1 Expression Is Associated with Decreased Efficacy of the Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cell Lines

2004 • 112 citations

Targeting cell cycle and hormone receptor pathways in cancer

2013 • 108 citations

CDK4/6 and IGF1 Receptor Inhibitors Synergize to Suppress the Growth of p16INK4A-Deficient Pancreatic Cancers

2014 • 108 citations

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

2014 • 108 citations

A Novel Therapeutic Combination Using PD 0332991 and Bortezomib: Study in the 5T33MM Myeloma Model

2008 • 107 citations

Efficacy of the combination of MEK and CDK4/6 inhibitorsin vitroandin vivoin KRAS mutant colorectal cancer models

2016 • 106 citations

Antiproliferative Effects of CDK4/6 Inhibition inCDK4-Amplified Human LiposarcomaIn VitroandIn Vivo

2014 • 105 citations

Aberrations of p16^Ink4 and retinoblastoma tumour‐suppressor genes occur in distinct sub‐sets of human cancer cell lines

1995 • 102 citations

Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt

2016 • 98 citations

PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity.

2013 • 96 citations

Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6

2012 • 96 citations

Correction: CDK4/ 6 inhibition provides a potent adjunct to Her2- targeted therapies in preclinical breast cancer models

2021 • 91 citations

Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells

2006 • 90 citations

Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo

2016 • 86 citations

CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma

2015 • 85 citations

Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

2015 • 85 citations

Proliferation: the Most Prominent Predictor of Clinical Outcome in Breast Cancer

2006 • 82 citations

Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma

2015 • 82 citations

Restoration of retinoblastoma mediated signaling to Cdk2 results in cell cycle arrest

2000 • 77 citations

Growth Factor, Steroid, and Steroid Antagonist Regulation of Cyclin Gene Expression Associated With Changes in T-47D Human Breast Cancer Cell Cycle Progression

1993 • 74 citations

Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer

2015 • 72 citations

Chemical inhibitors of cyclin-dependent kinases

1995 • 69 citations

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

2006 • 69 citations

The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death

1999 • 68 citations

Retinoblastoma Pathway Defects Show Differential Ability to Activate the Constitutive DNA Damage Response in Human Tumorigenesis

2006 • 66 citations

Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells

2012 • 64 citations

p16^INK4a‐induced senescence is disabled by melanoma‐associated mutations

2008 • 59 citations

Cell Cycle Machinery:

2008 • 59 citations

Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA

2015 • 56 citations

Cyclins and breast cancer

1996 • 56 citations

Characterization of t(11;14) translocation in mantle cell lymphoma by fluorescent in situ hybridization.

1996 • 49 citations

Early G1 Cyclin-Dependent Kinases as Prognostic Markers and Potential Therapeutic Targets in Esophageal Adenocarcinoma

2011 • 49 citations

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

2016 • 48 citations

CDK4/6 Inhibition Controls Proliferation of Bladder Cancer and Transcription of RB1

2015 • 43 citations

Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience

2005 • 41 citations

Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression

2011 • 40 citations

The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

2014 • 40 citations

Targeting Cyclin-Dependent Kinases in Synovial Sarcoma: Palbociclib as a Potential Treatment for Synovial Sarcoma Patients

2016 • 34 citations

Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer

2016 • 29 citations

The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer

2013 • 25 citations

Regulation of CYL /Cyclin D Genes by Colony‐Stimulating Factor 1

2007 • 25 citations

Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

2015 • 21 citations

CDK4/6 inhibitor suppresses gastric cancer with CDKN2A mutation.

2015 • 20 citations

p27kip1 Protein Levels Reflect a Nexus of Oncogenic Signaling during Cell Transformation

2012 • 8 citations