Abstract 3815: Overcoming acquired resistance of Lapatinib in breast cancer with Palbociclib

Abstract

Abstract Background : Lapatinib is a dual tyrosine kinase inhibitor that interrupts the ErbB family pathways in many solid tumors. However, the vast majority of patients who initially respond to the treatment will eventually relapse due to acquired resistance. The defects in cell cycle regulation via increased levels of cyclin D-CDK4/6 complex is well known mechanism of the acquired resistance to lapatinib. Thus, CDK4/6 inhibition can be considered as an attractive strategy to overcome lapatinib resistance. In this study, we investigated whether palbociclib, a palbociclib can overcome the resistance to lapatinib by modulating cell cycle regulation. Methods : Acquired resistant SK-BR-3-cells was established by treating lapatinib consistently. The features of lapatinib resistance (LR) cell lines were evaluated by MTT, FACS, Western blotting, qPCR, methylation assay and WES. The antitumor effects of palbociclib in LR cell lines were evaluated through changes in cell cycle progression, proliferative ability and signaling transduction. Results : In LR cell lines, the change of the molecules that were related to G1/S transition of cell cycle was prominent. It was confirmed that cell cycle progression and proliferation were significantly faster in LR cells compared to parental cells. Upregulation of cyclin D1, CDK4, CDK6 was shown in LR cells but cyclin-dependent kinase inhibitor, p16 was downregulated. The increase of Cyclin D1, CDK4, and CDK6 occur at the transcription level, and the epigenetic alteration of CDKN2A was observed. We identified that the palbociclib inhibited the cell cycle progression and reduced the cell viability significantly in LR cells by cell cycle arrest via blocking hyperphosphorylation of Rb. It was also confirmed that these changes resulted in apoptosis. Conclusion : The changes of cell cycle molecules that were related to G1/S transition was observed in LR cells. Upregulation of cyclin D1, CDK4, CDK6, and deficiency in CDKN2A led to the increasing cell cycle progression and prolfieration in LR cells. Therefore, inhibition of these molecules by palbociclib could be an effective strategies for overcoming lapaitnib resistance. Citation Format: Da Eun Jeong, Ahrum Min, Seongyeong Kim, So Hyeon Kim, Yoonjung Park, Yaewon Yang, Kyung-Hun Lee, Seock-Ah Im. Overcoming acquired resistance of Lapatinib in breast cancer with Palbociclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3815.