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

다국어 초록 (Multilingual Abstract)

<P>These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3<SUP>high</SUP> immune-refractroy cancer.</P><P>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<SUP>high</SUP> 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<SUP>high</SUP> 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<SUP>high</SUP> immune-refractory cancer.</P><P><B>Significance:</B> These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3<SUP>high</SUP> immune-refractroy cancer. <I>Cancer Res; 78(10); 2638–53. ©2018 AACR</I>.</P>