In:
Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 11_Supplement ( 2016-11-01), p. A12-A12
Abstract:
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 & lt; 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 concentration-dependent inhibition of CDK4/CDK6. Abemaciclib washout studies following longer-term exposure in T47-D (ER+/HER2-) demonstrated durable cell cycle inhibition resulting in significant inhibition of pRb_s807/811 even after the removal (washout) of abemaciclib while longer exposure also resulted in inhibition of estrogen receptor-α (ERα) expression in a panel of ER+ breast cancer cell lines that were evaluated over a 8 day time course. Using taqman low density RNA array (TLDA) cards designed with known ERα driven transcriptional targets, we investigated the impact of abemaciclib single agent and in combination with fulvestrant on changes in RNA expression in four day treated breast cancer cells (ER+/HER2-). Single agent abemaciclib appeared to inhibit a subset of ERα driven targets including TFF1, GREB1, ESR1, E2F1, CDC45, FOXM1 and IGFBP4 (inhibition & gt;%50). Interestingly, comparing single agent (% inhibition) abemaciclib to fulvestrant monotherapy in MCF-7 cells, we found that abemaciclib inhibited CDC45, E2F1, ESR1 and FOXM1 to a greater extent than that observed for these same targets following monotherapy with fulvestrant. Combining abemaciclib with fulvestrant identified an additional sub-group of ERα driven targets whereby the combination provided greater inhibition than that observed with any of the single agent treatments (IGFBP4, E2F1, FOXM1 and CDC45). Additionally, the combination treatment as compared to single-agent treatments also induced greater inhibition of various cell cycle regulatory genes including MCM7, CDKN2C, TOP2a, RRM2, and MKi67. Citation Format: Ann M. McNulty, Teresa Burke, Jack A. Dempsey, Christophe C. Marchal, Andrew E. Schade, Hadrian P. Szpurka, Michele S. Dowless, Jennifer Stephens, Jennifer Stephens, Denise Edmondson, Keith Stayrook, William C. Caldwell, Sean Buchanan, Farhana F. Merzoug, Richard P. Beckmann. The CDK4/CDK6 inhibitor abemaciclib inhibits transcriptional targets which facilitate growth in ER+ breast cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A12.
Type of Medium:
Online Resource
ISSN:
1541-7786
,
1557-3125
DOI:
10.1158/1557-3125.CELLCYCLE16-A12
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2097884-4
SSG:
12
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