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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 
 CANCER RESEARCH, Vol.78(10) : 2638-2653, 2018 
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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 NANOG(high) 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 SCP3(high) 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 SCP3(high) immune-refractory cancer.Significance: These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3(high) immune-refractroy cancer. Cancer Res; 78(10); 2638-53. (c)2018 AACR.
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1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Hoon(김재훈) ORCID logo https://orcid.org/0000-0001-6599-7065
Cho, Hanbyoul(조한별) ORCID logo https://orcid.org/0000-0002-6177-1648
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