Abstract 3074: Broad spectrum activity of the BET inhibitor GSK 1324726A in hematologic and solid cancer cell lines in-vitro and determination of associated predictive biomarkers
Authors: Fiebig Heinz-Herbert , Kelter Gerhard , Hendriks Hans R , Vuaroqueaux Vincent 
Published: August 2019

The BET family of bromodomain proteins (BRD2, BRD3, BRD4, and BRDT) has emerged as a promising new cancer target for small-molecule drug discovery. GSK 1324726A (I-BET726) is a highly selective inhibitor of BET family proteins that binds BRD2, BRD3 and BRD4 with IC50 of 41 nM, 31 nM, and 22 nM, respectively. In the present study, we aimed to identify sensitive tumor types for GSK 1324726A and predictive biomarkers for response or resistance. GSK 1324726A was tested in vitro in a 2D monolayer assay in 274 human tumor cell lines of 36 tumor types (50 liquid and 224 solid cancer cell lines). Antitumor activity was then tested in vivo in 5 of the most sensitive tumor cell lines transplanted sc in nude mice. Drug sensitivity results in vitro were correlated with molecular data of the tumor models, including whole exome mutations, gene copy number variations and gene expression profiles.

GSK 1324726A showed a moderate anti-tumor potency (median IC70 6,6 µM, range 0.03 - &gt;30 µM) and a pronounced selectivity in a wide range of blood and solid cancer cell lines. AML, ALL, multiple myelomas and B-cell lymphomas were 1 log more sensitive than the most sensitive solid tumors. Taking 10% of the median IC70 of all tumors as cut off (0.66 µM) 5/11 AML, 4/9 ALL, 5/11 MM and 7/13 B-NHL were sensitive. Among the solid tumor panel cervix uterus and prostate models were sensitive (2/5) followed by breast, soft tissue, CRC, ovarian cancers and melanomas (between 17 and 40%). In-vivo experiments of the most sensitive tumors are under way. The MTD of GSK 1324726A (po for 15 days) was 15 mg/kg/day as it effected a slight body weight loss of 4% and no lethality.

Evaluation of tumor cell lines for molecular parameters associated with response was carried out separately for hematologic and solid cell lines. For the leukemias, lymphomas and myelomas about 100 genes were significantly associated with response to GSK 1324726A at the transcriptome level (intersection of Spearman and Limma tests, adjusted p values &lt;0.05). JAG1 was identified as the most significant gene among them. JAG1 is known to interact with receptors in the Notch signaling pathway and regulate cell fate decisions. Solid tumor models did not show a strong predictive gene pattern. Integrative analysis with significant genomic and transcriptomic parameters is currently ongoing to develop a molecular predictor of response to GSK 1324726A. Extending evaluation of the compound in vivo and continuing investigation of predictors of response are underway.

Citation Format: Heinz-Herbert Fiebig, Gerhard Kelter, Hans R Hendriks, Vincent Vuaroqueaux. Broad spectrum activity of the BET inhibitor GSK 1324726A in hematologic and solid cancer cell lines in-vitro and determination of associated predictive biomarkers [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 3074.