EXTH-36. PHARMACEUTICAL INHIBITION OF CYCLIN DEPENDENT KINASE 4/6 (CDK4/6) IN GLIOBLASTOMA

Abstract

Abstract Potent and selective CDK4/6 inhibitors (CDK4/6i) have potential for treating glioblastoma. Although genomic abnormalities affecting CDK4/6-RB1 signaling axis, such as CDK4 or CDK6 amplification and CDKN2A deletion, which are frequent in GBM, have been proposed to predict response of RB1-wildtype GBM to CDK4/6i, there is not enough data validating these biomarkers as sufficient for patient selection. Here we employ a panel of GBM patient derived cancer stem cells (CSC) representing the most frequent somatic genomic alterations in GBM to test their response to CDK4/6i. Twelve CSC lines were treated in quintuplicate for 4–7 days with 0–10 mM Abemaciclib, Ribociclib or vehicle control. Cell viability was measured using CellTiterGlo and dose response curves were analyzed using GRmetrics in R to determine Area Above the Curve (AAC) and IC50, factoring variable growth rates among cell lines. Experiments were repeated 2–4 times. Abemaciclib was more potent in reducing cell viability, based on the RB1-null CSC line measured resistance (mean AAC = 0.3 +/- 0.06), ribociclib was more specific (mean AAC = 0.05 +/-0.01). 4/7 CSCs with CDKN2A homozygous deletion were sensitive (mean AAC > 0.7) while 3/7 were resistant (mean AAC < 0.33) to 4 and 7-day treatments of abemaciclib. One CSC from a newly diagnosed GBM bearing CDK4, MYC and EGFR amplifications was sensitive to both inhibitors (mean AAC = 0.5 abemaciclib and ribociclib), while CSC from the matched recurrent tumor presenting the same driver genomic alterations was significantly more resistant (mean AAC = 0.2 for abemaciclib and ribociclib) (p < 0.05, t-test). Additionally, we exposed a sensitive cell line to conditioned media from a resistant cohort, resulting in significantly reduced proliferation and increased resistance to CDK4/6i (p< 0.05, Dunn). These findings underscore the importance of a utilizing a robust molecular profiling approach in evaluating which patients will benefit from CDK4/6i therapy.