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