Abstract 274: The ATR inhibitor BAY 1895344 shows strong preclinical activity in lymphomas and appears associated with specific gene expression signatures
Authors: Gaudio Eugenio , Tarantelli Chiara , Spriano Filippo , Cascione Luciano , Arribas Alberto , Zucca Emanuele , Stathis Anastasios , Wengner Antje Margret , Bertoni Francesco 
Published: August 2019

Introduction. Targeting the DNA repairing pathways represents an intriguing new approach for cancer treatment. BAY 1895344 is a potent, highly selective and orally available ATR inhibitor (Luecking et al, AACR 2017) in its early clinical development in patients with advanced solid tumors and lymphomas (NCT03188965). We performed evaluated its antitumor activity in a large panel of lymphoma cell lines.

Methods. IC50s and caspase 3/7 activation were obtained in cell lines derived from human B (n=50) or T cell (n=9), murine (n=2) and canine (n=1) lymphomas exposed to increasing doses of BAY 1895344 for 72h. Apoptosis activation was defined by at least 1.5-fold increase in caspase 3/7 signal activation vs controls. Transcriptome data (Illumina HumanHT 12 Expression BeadChips, HTG Biomarker Panel) were analyzed with GSEA (statistical significance: absolute NES &gt;1.5, FDR &lt; 0.01). In vivo efficacy was evaluated in xenograft studies of human lymphoma in mice.

Results. BAY 1895344 showed anti-tumor activity with a median IC50 of 60 nM (95%C.I.; 3-500 nM) across the 62 cell lines, comprising mainly germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL, n.=17), activated B-cell DLBCL (8), mantle cell lymphoma (MCL, 10), marginal zone lymphoma (6), T cell lymphomas (9). BAY 1895344 was mostly cytotoxic with apoptosis induction in 38/62 (61%) of the cell lines. Sensitivity was not affected by lymphoma histology or DLBCL cell of origin, TP53/BCL2/MYC status or ATM/ATR loss.

A xenograft experiment (MCL Rec-1 cell line) demonstrated complete tumor remission with BAY 1895344 (50 mg/kg, twice daily, 3 days on and 4 days off).

Comparing the gene expression profile of 4 less (IC50&gt;200nM) vs 3 very sensitive (IC50&lt;10nM) GCB-DLBCL cell lines, cell cycle regulation and DNA repair genes were positively associated with higher sensitivity (E2F targets; G2M checkpoint; DNA repair), while survival and inflammation transcripts with lower (TNFA signaling; IL2/STAT5 signaling). Similar results for E2F targets, G2M checkpoint, TNFA signaling and IL2/STAT5 signaling were confirmed in MCL cell lines. Finally, we compared the transcriptome obtained using an NGS-based platform in 30 B cell lymphoma cell lines divided by the median IC50. Genes involved in BRCA1 and/or ATM networks, RB1 and/or TP53 targets, WNT signaling were higher in the most sensitive cell lines, while the opposite was true for genes taking part to apoptosis, cytokine interaction pathway, inflammatory response and TNFA signaling via NFκB, and MAPK signaling.

Conclusion. A strong anti-tumor activity, associated with specific gene expression signatures, was seen with BAY 1895344 in lymphoma models, providing further support for the on-going phase I study.

Citation Format: Eugenio Gaudio, Chiara Tarantelli, Filippo Spriano, Luciano Cascione, Alberto Arribas, Emanuele Zucca, Anastasios Stathis, Antje Margret Wengner, Francesco Bertoni. The ATR inhibitor BAY 1895344 shows strong preclinical activity in lymphomas and appears associated with specific gene expression signatures [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 274.