Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy

Journal Article · · npj Breast Cancer
 [1];  [2];  [1];  [3];  [1];  [2];  [1];  [1];  [1];  [2];  [2];  [2];  [1];  [1];  [1];  [3];  [1];  [1];  [3];  [3] more »;  [4];  [2];  [1] « less
  1. Eli Lilly and Company, Madrid (Spain)
  2. Eli Lilly and Company, San Diego, CA (United States)
  3. Eli Lilly and Company, Indianapolis, IN (United States)
  4. Eli Lilly and Company, New York, NY (United States)
+ Show Author Affiliations
Despite the biological and therapeutic relevance of CDK4/6 for the treatment of HR+, HER2- advanced breast cancer, the detailed mode of action of CDK4/6 inhibitors is not completely understood. Of particular interest, phosphorylation of CDK4 at T172 (pT172) is critical for generating the active conformation, yet no such crystal structure has been reported to date. We describe here the x-ray structure of active CDK4-cyclin D3 bound to the CDK4/6 inhibitor abemaciclib and discuss the key aspects of the catalytically-competent complex. Furthermore, the effect of CDK4/6 inhibitors on CDK4 T172 phosphorylation has not been explored, despite its role as a potential biomarker of CDK4/6 inhibitor response. We show mechanistically that CDK4/6i stabilize primed (pT172) CDK4-cyclin D complex and selectively displace p21 in responsive tumor cells. Stabilization of active CDK4-cyclin D1 complex can lead to pathway reactivation following alternate dosing regimen. Consequently, sustained binding of abemaciclib to CDK4 leads to potent cell cycle inhibition in breast cancer cell lines and prevents rebound activation of downstream signaling. Overall, our study provides key insights demonstrating that prolonged treatment with CDK4/6 inhibitors and composition of the CDK4/6-cyclin D complex are both critical determinants of abemaciclib efficacy, with implications for this class of anticancer therapy.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2423333
Journal Information:
npj Breast Cancer, Journal Name: npj Breast Cancer Journal Issue: 1 Vol. 8; ISSN 2374-4677
Publisher:
Springer NatureCopyright Statement
Country of Publication:
United States
Language:
English

References (43)

Adjuvant cyclin‐dependent kinase 4/6 inhibition in hormone receptor–positive breast cancer: One Monarch to rule them all? journal May 2021
MolProbity: More and better reference data for improved all-atom structure validation: PROTEIN SCIENCE.ORG journal November 2017
HDX Workbench: Software for the Analysis of H/D Exchange MS Data journal June 2012
A Decoupled Automation Platform for Hydrogen/Deuterium Exchange Mass Spectrometry Experiments journal November 2019
Physical interaction of the retinoblastoma protein with human D cyclins journal May 1993
Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders journal October 2020
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 journal April 2016
Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition journal April 2020
Hallmarks of Cancer: The Next Generation journal March 2011
A Cdk7-Cdk4 T-Loop Phosphorylation Cascade Promotes G1 Progression journal April 2013
Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1 journal November 2019
Toward Understanding the Structural Basis of Cyclin-Dependent Kinase 6 Specific Inhibition journal May 2006
Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex journal July 1995
G1 cell-cycle control and cancer journal November 2004
Cell cycle kinases as therapeutic targets for cancer journal July 2009
Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2 journal June 2021
Unlocking PDAC initiation with AP-1 journal January 2021
Palbociclib and Letrozole in Advanced Breast Cancer journal November 2016
Crystal structure of human CDK4 in complex with a D-type cyclin journal February 2009
The structure of CDK4/cyclin D3 has implications for models of CDK activation journal February 2009
Differential Interaction of the Cyclin-dependent Kinase (Cdk) Inhibitor p27Kip1 with Cyclin A-Cdk2 and Cyclin D2-Cdk4 journal October 1997
Structural insights into the functional diversity of the CDK–cyclin family journal September 2018
New functional activities for the p21 family of CDK inhibitors. journal April 1997
Phaser crystallographic software journal July 2007
Features and development of Coot journal March 2010
Data processing and analysis with the autoPROC toolbox journal March 2011
Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER journal March 2012
Towards automated crystallographic structure refinement with phenix.refine journal March 2012
How good are my data and what is the resolution? journal June 2013
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix journal October 2019
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase journal June 2016
p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition journal December 2019
Differential Modification of p27 Kip1 Controls Its Cyclin D-cdk4 Inhibitory Activity journal January 2008
Induced Expression of p16 INK4a Inhibits Both CDK4- and CDK2-Associated Kinase Activity by Reassortment of Cyclin-CDK-Inhibitor Complexes journal March 1999
Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance journal August 2016
Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2−, Node-Positive, High-Risk, Early Breast Cancer (monarchE) journal December 2020
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy journal September 2017
MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer journal November 2017
CDK4 T172 Phosphorylation Is Central in a CDK7-Dependent Bidirectional CDK4/CDK2 Interplay Mediated by p21 Phosphorylation at the Restriction Point journal May 2013
Preclinical characterization of abemaciclib in hormone receptor positive breast cancer journal May 2017
The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes journal September 2014
Autocatalytic Phosphorylation of CDK2 at the Activating Thr160 journal April 2007
Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy dataset January 2022

Cited By (3)

Patients’ preferences for postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treatments in Japan journal April 2019
Two may be better than one: PD-1/PD-L1 blockade combination approaches in metastatic breast cancer journal October 2019
Beyond Tumor Suppression: Senescence in Cancer Stemness and Tumor Dormancy journal February 2020

Similar Records

Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1
Journal Article · Tue Jul 01 00:00:00 EDT 2008 · Experimental Cell Research · OSTI ID:21128140
Cyclin D1 blocks the anti-proliferative function of RUNX3 by interfering with RUNX3-p300 interaction
Journal Article · Fri Sep 24 00:00:00 EDT 2010 · Biochemical and Biophysical Research Communications · OSTI ID:22202782
Targeting the AKT/GSK3{beta}/Cyclin D1/Cdk4 Survival Signaling Pathway for Eradication of Tumor Radioresistance Acquired by Fractionated Radiotherapy
Journal Article · Wed Jun 01 00:00:00 EDT 2011 · International Journal of Radiation Oncology, Biology and Physics · OSTI ID:21491775

Related Subjects

60 APPLIED LIFE SCIENCES
Oncology