Abstract 3260: Potentiation of Type I interferon signaling leads to in vivo efficacy achieved with combination of chemotherapy and the PARP7 inhibitor RBN-2397
Authors: Kunii Kaiko , Song Jeff J. , Zimmerman Danielle , Liu Chang , Kuplast-Barr Kristy G. , Novak Jonathan J. , Nayak Sunaina P. , Gozgit Joseph M. , Vasbinder Melissa M. , McEachern Kristen , Kuntz Kevin W. , Keilhack Heike , Molina Jennifer R. 
Published: June 2023

Abstract
There are many pathways that activate the Type I interferon (IFN) response to combat tumor progression including the cytosolic nucleic acid sensing pathways. PARP7 is a monoART enzyme that was reported to negatively regulate the Type I IFN response by interacting with TBK1 during viral infection. We and others have demonstrated that PARP7 is a novel negative regulator of cytosolic nucleic acid sensing in tumor cells. RBN-2397 is the first potent and selective small molecule inhibitor of PARP7 catalytic function. We have shown that administration of RBN-2397 to CT26 tumor-bearing mice significantly decreased tumor growth and led to complete and durable regressions in a subset of mice. The antitumor effects correlated with activation of p-STAT1 and increased expression of ISGs including CXCL10, MX1, and CCL5 in tumors. A growing body of work has shown that DNA damaging agents such as chemotherapies activate the Type I IFN response by generating accumulation of nucleic acids, including DNA, in the cytosol or tumor microenvironment. These aberrant cytosolic nucleic acids are recognized by the innate immune response via cGAS leading to activation of the STING/TBK pathway and subsequent production of IFN-β and expression of ISGs (interferon induced genes). Given that PARP7 suppresses the Type I IFN response, we hypothesized that the immune-related mechanism observed with chemotherapy would be inhibited in tumors with high PARP7 expression. Combining chemo with RBN-2397 could potentiate Type I IFN response activation in PARP7 expressing tumors and enhance immune mediated anti-tumor responses. We tested the ability of platinum (cisplatin, oxaliplatin, and carboplatin) and taxane (docetaxel and paclitaxel) chemotherapy agents to activate the Type I IFN response in the CT26 mouse colon cancer cell line in vitro by gene expression analysis of several ISGs (CXCL10, CCL5, MX1, IFIT1, and IFN-β). Single agent chemo led to modest increases in the expression of ISGs. The combination of cisplatin or oxaliplatin with RBN-2397 significantly potentiated the effect of RBN-2397 and led to a synergistic increase of the ISGs in CT26 cells after 24 hours of treatment. Similar effects were obtained with the combination of docetaxel or paclitaxel with RBN-2397. To evaluate if the combinatorial effect observed in vitro translated into increased efficacy in vivo, we first identified doses of single agent cisplatin or docetaxel that increased expression of ISGs and enhanced cytosolic-DNA in CT26 tumors. Next, we verified the tolerability of validated doses in combination with RBN-2397. Finally, we performed an efficacy study in CT26 tumor bearing mice and observed that the combination of cisplatin and RBN-2397 increased tumor growth inhibition and survival relative to single agent activity. This study provides rationale for exploration of DNA damaging agents in combination with RBN-2397.
Citation Format: Kaiko Kunii, Jeff J. Song, Danielle Zimmerman, Chang Liu, Kristy G. Kuplast-Barr, Jonathan J. Novak, Sunaina P. Nayak, Joseph M. Gozgit, Melissa M. Vasbinder, Kristen McEachern, Kevin W. Kuntz, Heike Keilhack, Jennifer R. Molina. Potentiation of Type I interferon signaling leads to in vivo efficacy achieved with combination of chemotherapy and the PARP7 inhibitor RBN-2397 [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 3260.