Abstract 4555: Aryl-hydrocarbon receptor inhibitors in combination with anticancer agents, especially proteasome pathway inhibitors, in a complex spheroid screen using patient-derived cell lines can result in greater-than additive cytotoxicity

Abstract

Abstract Three aryl-hydrocarbon receptor (AhR) selective inhibitors, BAY-2416964, GNF351 and CH-223191, were assayed alone and in combination with 25 approved or investigational anticancer agents in complex spheroids including tumor cells, endothelial cells, and mesenchymal stem cells. The tumor cell lines were from the National Cancer Institute’s Patient-Derived Models Repository (PDMR) collection (https://pdmr.cancer.gov/models/database.htm). The AhR is a ligand-activated helix-loop-helix transcription factor of the bHLH-PAS family. It is involved in the regulation of responses to planar aromatic hydrocarbons by activating the transcription of xenobiotic-metabolizing enzymes such as cytochrome P450 or by acting as an E3 ligase. Thus, the AhR activates detoxification pathways that dispose of small molecule toxins and damaged proteins. In the absence of xenobiotics, the AhR is located within the cytoplasm in complex with two Hsp90 molecules and co-chaperones. Upon xenobiotic binding, the AhR translocates to the nucleus and binds to the AhR nuclear translocator protein to form an active transcription factor complex and promote gene transcription. As single agents, the three AhR inhibitors showed little cytotoxicity at concentrations up to 10 µM. Combinations of AhR inhibitors with anticancer agents including doxorubicin, cisplatin, SN38, venetoclax, selinexor, and etoposide (https://dtp.cancer.gov/organization/dscb/obtaining/default.htm) produced primarily additive cytotoxicity in complex spheroids after a 7-day exposure. However, unexpected greater-than-additive effects were observed with AhR inhibitors in combination with proteasome pathway inhibitors. Bortezomib, a direct inhibitor of the chymotrypsin-like protease of the 26S proteasome, and pevonedistat, a NEDD8-activating enzyme inhibitor, produced additive or greater-than-additive cytotoxicity in some complex spheroids. However, the combination of BAY-2416964 with TAK-243, a ubiquitin activating enzyme inhibitor, produced profound greater-than-additive cytotoxicity in more than half of the 28 PDMR cell lines tested as complex spheroids. The combination resulted in an increase of 1- to 3-logs of excess cytotoxicity in malignancies including bladder cancer, pancreatic cancer, colon cancer, NSCLC, SCLC and glioblastoma. In vivo studies are under discussion. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: BEVERLY A. TEICHER, Jeffrey A. Moscow, Joel Morris, James H. Doroshow, Thomas S. Dexheimer, Nathan P. Coussens, Thomas Silvers, Rene Delosh, Zahra Davoudi, Russel Reinhart, Chad Ogle, Eric Jones. Aryl-hydrocarbon receptor inhibitors in combination with anticancer agents, especially proteasome pathway inhibitors, in a complex spheroid screen using patient-derived cell lines can result in greater-than additive cytotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4555.