PUBLICATION

Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3-NANOG Axis

Authors
Oh, S.J., Cho, H., Kim, S., Noh, K.H., Song, K.H., Lee, H.J., Woo, S.R., Kim, S., Choi, C.H., Chung, J.Y., Hewitt, S.M., Kim, J.H., Baek, S., Lee, K.M., Yee, C., Park, H.C., Kim, T.W.
ID
ZDB-PUB-190614-23
Date
2018
Source
Cancer research   78: 2638-2653 (Journal)
Registered Authors
Kim, Suhyun, Park, Hae-Chul
Keywords
none
MeSH Terms
  • Animals
  • Cell Line, Tumor
  • Cyclin D1/antagonists & inhibitors*
  • Cyclin D1/metabolism
  • Cyclin-Dependent Kinase 4/antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4/metabolism
  • Cyclin-Dependent Kinase 6/antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6/metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Immunotherapy/methods
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nanog Homeobox Protein/genetics
  • Nanog Homeobox Protein/metabolism*
  • Neoplasms/drug therapy*
  • Neoplasms/pathology
  • Nuclear Proteins/genetics
  • Nuclear Proteins/metabolism*
  • Piperazines/pharmacology*
  • Protein Kinase Inhibitors/pharmacology*
  • Pyridines/pharmacology*
  • RNA Interference
  • RNA, Small Interfering/genetics
  • Zebrafish
PubMed
29437706 Full text @ Cancer Res.
Abstract
Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1-CDK4/6 axis. The SCP3-cyclin D1-CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3high immunoedited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3high immune-refractory cancer.Significance: These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3high immune-refractroy cancer. Cancer Res; 78(10); 2638-53. ©2018 AACR.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes
This article is corrected by ZDB-PUB-220906-113 .