Abstract 2318: Palbociclib, a CDK4/6 inhibitor, suppresses proliferation of triple negative breast cancer

Abstract

Abstract Background: Abnormal cell cycle progression is a characteristic of cancer and targeting the cell cycle is a strategy for cancer treatment. TCGA reported that Cyclin D1 is overexpressed in 25% to 60% of invasive breast carcinomas, and CDK4/6 and CDKN2A/B aberrations are observed in 7.6% of breast cancer cases. Palbociclib is a specific inhibitor of CDK4/6, a key regulator of the G1 checkpoint. In hormone receptor positive breast cancer, the addition of palbociclib to endocrine treatment either aromatase inhibitor or fulvestrant significantly prolonged PFS in phase III trials. However, the effects of palbociclib have not been fully examined in triple negative breast cancer (TNBC) yet, although CCND amplification and CDKN2A loss are frequently observed in TNBC. Therefore, we investigated the effects of palbociclib on TNBC cells and attempted to identify the underlying mechanisms of palbociclib. Methods: The cytotoxicity assay, cell cycle analysis and western blotting were conducted to determine anti-tumor effect and action mechanisms of palbociclib on breast cancer cell lines. These in vitro data were validated in vivo model as well. Results: Human breast cancer cell lines showed heterogeneous response to palbociclib. Palbociclib induced G1 cell cycle arrest by blocking Rb phosphorylation, and inhibited cell proliferative signaling. In sensitive TNBC cells, palbociclib promoted senescence rather than apoptosis. In addition, palbociclib enhanced the antitumor effect of 5-FU by modulating thymidine synthase (TS) and E2F1 expression. The anti-tumor effects of palbociclib on TNBC cells were validated in TNBC-xenograft model as well. Conclusions: CDK4/6 inhibitor palbociclib showed anti-tumor effect in vitro and in vivo xenograft model of TNBC and acts synergistically with 5-FU by downregulating TS. Our results suggest that palbociclib has therapeutic potential for the treatment of TNBC, not limited in hormone positive breast cancer type. Our results provide a rationale for the future clinical trials of palbociclib in the treatment of breast cancers. Citation Format: Ahrum Min, Yu Jin Kim, Hyemin Hang, Jee Min Lim, Seongyeong Kim, So Hyeon Kim, Koung Jin Suh, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. Palbociclib, a CDK4/6 inhibitor, suppresses proliferation of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2318.