Abstract 2060: Characterizing acquired resistance to palbociclib in breast cancer

Abstract

Abstract The CDK4/6 inhibitor palbociclib is currently being used in combination with endocrine therapy to treat advanced ER positive breast cancer patients. While this treatment has shown great promise in the clinic, about 25% of the patients do not respond, and almost all patients eventually acquire resistance to palbociclib treatment. Hence, understanding the mechanism(s) of acquired resistance to CDK4/6 inhibition is crucial to devise alternate treatment strategies. To interrogate this, we developed MCF7 and T47D resistant cells by treating them with increasing doses of palbociclib over a 6-month period. After confirming that these cells were resistant to palbociclib, we performed genome-wide expression analysis via RNA-seq, in comparison with the parental (sensitive) cells. RNA- seq analysis revealed 2888 differentially expressed genes (p<0.05) in the resistant cells when compared to parental. Further, gene set enrichment analysis (GSEA) revealed enrichment of immune pathways (interferon alpha and gamma response, immune response) and pathways known to regulate EMT and cancer stem cells (IL-6/Stat3, IL-2/STAT-5, Notch, Wnt) in the resistant cells. Additionally, GSEA analysis revealed downregulation of G2/M checkpoint, estrogen response and DNA repair pathways (double strand break repair). Thus, this data suggests that combined targeting of two or more pathways that are altered in the resistant cells can provide a novel therapeutic strategy to combat CDK4/6 inhibitor resistance. Citation Format: Smruthi Vijayaraghavan, Iman Doostan, Jason P.W. Carey, Khandan Keyomarsi. Characterizing acquired resistance to palbociclib in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2060. doi:10.1158/1538-7445.AM2017-2060