Abstract A12: The CDK4/CDK6 inhibitor abemaciclib inhibits transcriptional targets which facilitate growth in ER+ breast cancer cells

Abemaciclib (LY2835219) is an ATP-competitive inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), which is currently undergoing clinical evaluation as a single-agent treatment and in combination with the anti-hormonal therapy (SERD) fulvestrant in estrogen receptor positive (ER+) breast cancer (BrCa). Breast cancer cell line (15 lines) sensitivity to treatment with abemaciclib was assessed using multiple approaches including EdU incorporation, phosphorylation of retinoblastoma protein at serine 807/811 (pRb_s807/811) and RNA transcriptional profiling. We identified molecular features including ER-positivity (ER+), and luminal histology, as key to greater sensitivity while loss of Rb was associated with lower sensitivity. Changes in the Modaplex based RNA transcriptional array profiles of 29 cell cycle related target genes across a panel of 15 human breast cancer cell lines further characterized sensitivity to abemaciclib and highlighted potential targets of response. A sub-group of targets including MKi67, E2F1, MCM7, FOXM1, RRM2 and TOPIIα were significantly inhibited in highly sensitive cell lines previously characterized with EC50 < 50nM (EdU, pRb_serine 807/811). Additionally, we looked at abemaciclib induced transcriptional changes in vivo treating nude mice bearing human, ER+ breast cancer (ER+/HER2-) tumor xenografts and found that the inhibition of expression of this same group of transcriptional targets plus CCNE1 and CDKN2C correlated with the concentra...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Poster Presentations - Proffered Abstracts Source Type: research