Targeting cyclin D-CDK4/6 sensitizes immune-refractory cancer by blocking the SCP3–NANOG axis

Se Jin Oh, Hanbyoul Cho, Suhyun Kim, Kyung Hee Noh, Kwon Ho Song, Hyo Jung Lee, Seon Rang Woo, Suyeon Kim, Chel Hun Choi, Joon Yong Chung, Stephen M. Hewitt, Jae Hoon Kim, Seungki Baek, Kyung Mi Lee, Cassian Yee, Hae Chul Park, Tae Woo Kim

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2638-2653
Number of pages16
JournalCancer Research
Volume78
Issue number10
DOIs
Publication statusPublished - 2018 May 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    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. (2018). Targeting cyclin D-CDK4/6 sensitizes immune-refractory cancer by blocking the SCP3–NANOG axis. Cancer Research, 78(10), 2638-2653. https://doi.org/10.1158/0008-5472.CAN-17-2325