Abstract PS5-40: CDKN2A loss can be a predictive marker of palbociclib in breast and gastric cancer
Authors: Min Ahrum , Kim Yu Jin , Lee Miso , Lee Kyung-Hun , Im Seock-Ah 
Published: February 2021

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 7% and 12% of gastric cancers exhibit CCND1 or CCNE1 alterations, respectively. Besides, Cyclin D1 is overexpressed in 25% to 60% of invasive breast carcinomas, and gene amplification is observed in 10% to 30% of breast cancer cases. Furthermore, CDK4/6 and CDNK2A/B aberrations are frequently observed in gastric (39.6%) and breast (7.6%) cancers. The presence of such abnormalities in cell cycle-related molecules suggests that gastric and breast cancers are good candidates for treatment with cell cycle inhibitors. Palbociclib is a specific inhibitor of CDK4/6, a vital regulator of the G1 checkpoint, and has been approved by the FDA because it provided a significant benefit by extending PFS in a phase III trial for hormone-positive advanced breast cancer. However, the predictive marker of palbociclib is not determined. Even though CDKN2A loss has been considered as a sensitive marker of palbociclib, there is no preclinical evidence to support whether CDKN2A deficient cancer shows sensitivity to palbociclib, especially in gastric and breast cancer. Therefore, we investigated the effects of palbociclib on CDKN2A loss gastric and breast cancer cell lines as well as patient derived-xenograft (PDX) models. Methods: The cytotoxic assay, cell cycle analysis, and western blotting were conducted to determine the anti-tumor effect and action mechanisms of palbociclib on gastric and breast cancer cell lines. Moreover, modulation of CDKN2A expression was conducted by siRNA and plasmid overexpression. These in vitro data were validated in vivo model and gastric cancer PDX models which have CDKN2A loss as well. Results: There is a meaningful correlation between CDKN2A loss and palbociclib sensitivity among gastric and breast cancer cell lines. CDKN2A loss cells showed G1 cell cycle arrest by blocking Rb phosphorylation and inhibited proliferative cell signaling. Moreover, palbociclib promoted senescence rather than apoptosis. The depletion of CDKN2A expression using siRNA increased palbociclib sensitivity with G1 cell cycle arrest accompanied by senescence. In contrast, CDKN2A overexpression in sensitive cells showed insensitivity to palbociclib. The anti-tumor effects of palbociclib on CDKN2A loss breast cancer cells were validated in the xenograft model, and the two different gastric cancer PDX
models have CDKN2A loss also showed a significant response to palbociclib as well. Conclusions: CDK4/6 inhibitor palbociclib showed an anti-tumor effect in vitro and in vivo xenograft model of CDKN2A loss gastric and breast cancer. Our results suggest that palbociclib has therapeutic potential for the treatment of not only breast cancer but also gastric cancer, not limited to a 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, Miso Lee, Kyung-Hun Lee, Seock-Ah Im. CDKN2A loss can be a predictive marker of palbociclib in breast and gastric cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-40.