Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells

Ahrum Min, Jung Eun Kim, Yu Jin Kim, Jee Min Lim, Seongyeong Kim, Jin Won Kim, Kyung Hun Lee, Tae Yong Kim, Do Youn Oh, Yung Jue Bang, Seock Ah Im

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Palbociclib is a specific inhibitor of CDK4/6 and has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer. TCGA database reported that about half of gastric cancers exhibit abnormalities in cell-cycle-related molecules, suggesting that gastric cancer is a good candidate for palbociclib treatment; however, the antitumor effects and predictive markers of palbociclib in gastric cancer remain incompletely described. Herein, the effect and predictive markers of palbociclib on gastric cancer cells were investigated. Our results reveal that palbociclib showed anti-proliferative effects by inducing G1 phase cell-cycle arrest and cellular senescence in some gastric cancer cells. Basal protein expression level of cyclin E showed an inverse correlation of cancer cell sensitivity to palbociclib. In addition, palbociclib enhanced the antitumor effect of 5-FU in vitro and in vivo by modulating thymidine synthase expression. These results suggest that cyclin E protein expression determines the anti-proliferative effect of palbociclib, and palbociclib acts synergistically with 5-FU in gastric cancer. These findings provide a rationale for future clinical trials of palbociclib and 5-FU combination-based chemotherapy in gastric cancer.

Original languageEnglish
Pages (from-to)123-132
Number of pages10
JournalCancer Letters
Volume430
DOIs
StatePublished - 28 Aug 2018

Keywords

  • 5-FU
  • Cell cycle
  • Cyclin E
  • Gastric cancer
  • Palbociclib

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