Abstract 836: ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models

Abstract

The integrity of the genome of eukaryotic cells is secured by complex signaling pathways, known as DNA damage response (DDR). Recognition of DNA damage activates DDR pathways resulting in cell cycle arrest, induction of DNA repair, or cell death. Proteins that directly recognize aberrant DNA structures recruit and activate kinases of the DDR pathway, such as ATR (ataxia telangiectasia and Rad3-related). ATR responds to a broad spectrum of DNA damage, including double-strand breaks (DSB) and lesions derived from interference with DNA replication as well as increased replication stress. Therefore, inhibition of ATR kinase activity could be the basis for a novel anti-cancer therapy in tumors with increased DNA damage, deficiency in DNA damage repair or replication stress. Radium-223 dichloride (Xofigo®) is the first and only approved targeted alpha therapy so far. It is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease, based on improvement of overall survival. It exhibits strong cytotoxic effects on adjacent cells via the induction of DNA DSB. Here, we disclose for the first time the structure and functional characterization of the novel ATR kinase inhibitor BAY 1895344. In vitro, BAY 1895344 is a selective low-nanomolar inhibitor of ATR kinase activity, potently inhibiting proliferation of a broad spectrum of human tumor cell lines (median IC50 of 78 nM). A clear separation between highly sensitive (IC50 <10 nM) and less sensitive cell lines was observed. The majority of the sensitive cell lines are characterized by mutations affecting the ATM (ataxia telangiectasia mutated) pathway. In cellular mechanistic assays BAY 1895344 inhibited hydroxyurea-induced H2AX phosphorylation demonstrating the anticipated mode of action. BAY 1895344 is an ATR inhibitor that exhibits strong in vivo anti-tumor efficacy in monotherapy in a variety of xenograft models of different indications that are characterized by DDR deficiencies, inducing stable disease in ovarian and colorectal cancer or even complete tumor remission in mantle cell lymphoma models. In addition, we could demonstrate that combination treatment with BAY 1895344 and Radium-223 exhibits clear synergistic anti-tumor activity in a bone metastases xenograft model of CRPC. Our findings validate the concept of synthetic lethality of genetically determined DNA repair deficiency and ATR blockade by demonstrating strong monotherapy efficacy of the highly potent ATR inhibitor BAY 1895344 in a variety of tumor indications. Furthermore, the mechanism-based combination potential of DNA damage induction by Radium-223 with BAY 1895344 creates a powerful new treatment option for CRPC patients with bone metastases. The start of clinical investigation of BAY 1895344 is planned early 2017. Citation Format: Antje Margret Wengner, Gerhard Siemeister, Ulrich Luecking, Julien Lefranc, Philip Lienau, Gesa Deeg, Eleni Lagkadinou, Li Liu, Sven Golfier, Christoph Schatz, Arne Scholz, Franz von Nussbaum, Michael Brands, Dominik Mumberg, Karl Ziegelbauer. ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 836. doi:10.1158/1538-7445.AM2017-836

Recent Advances in Prostate Cancer Treatment and Drug Discovery

“…Another approach is the inhibition of ataxia telangiectasia and Rad3-related kinase (ATR), which senses single-strand DNA breaks [ 83 ]. Potent anti-tumor efficacy was observed for the ATR inhibitor BAY 1895344 in combination with radium-223 dichloride in a bone metastasis xenograft model of CRPC [ 84 ]. Chk1 is a cell-cycle regulator of DNA damage response downstream of ATR and recent data show its inhibitor AZD7762 to be additive or synergistic with enzalutamide in prostate cancer xenografts [ 85 ]; however clinical studies with this compound have been discontinued.…”

“…In vivo experiments performed in prostate cancer xenograft models show that once deposited in the newly formed intra-tumoral bone matrix, radium-223 dichloride has cytotoxic effects on adjacent tumor cells, osteoclasts and disease-promoting osteoblasts by inducing difficult-to-repair DNA double-strand breaks, thereby disrupting positive feedback loops between tumor microenvironment cells and osteoblasts [ 120 ]. Preclinical evidence for synergistic effects with the ATR inhibitor BAY 1895344 has been reported [ 84 ].…”

Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand

“…AZD6738 is an orally active ATR inhibitor developed by AstraZeneca that has been shown in vitro to inhibit ATR kinase activity at IC 50 of 1 nM and CHK1 phosphorylation at IC 50 of 74 nM [13]. AZD6738 was shown to suppress both solid and hematological cell lines with an IC 50 of less than 1 μM [14, 32, 33]. Synthetic lethality was observed with AZD6783 in gastric cancer, non-small cell lung cancer (NSCLC), and chronic lymphocytic leukemia (CLL) cell lines that were ATM deficient [13, 32].…”

“…BAY1895344 is an ATR inhibitor developed by Bayer that is used to inhibit the proliferation of human cancer cell lines with a median IC 50 of 78 nM. Most sensitive cell lines are characterized by mutations of the ATM-associated pathway [14]. The synergy between BAY1895334 and radium-223, an FDA-approved alpha radiopharmaceutical, was observed in a bone metastasis xenograft model of castration-resistant prostate cancer [14].…”

Clinically Applicable Inhibitors Impacting Genome Stability

“…AZD6738 is currently enrolled in 10 phase I/II trials against multiple cancer types (including CLL, breast cancer, high-grade carcinomas, NSCLC) [ 201 , 202 , 203 ]. BAY-1895344 is a potent, orally available and selective ATR (kinase activity) inhibitor that in vivo exhibited strong antitumour efficacy as a monotherapy in a variety of DNA damage deficient preclinical xenograft tumour models (ovarian, colorectal prostate and cell lymphoma models) [ 189 ]. Currently, BAY-1895344 is in a phase I trial (NCT03188965) as a monotherapy treatment for advanced solid tumours and lymphomas ( Table 4 ).…”