Abstract 1633: ADT-030, a novel dual-acting RAS and β-catenin inhibitor with robust antitumor activity
Authors: Ramirez-Alcantara Veronica , Chen Xi , Schuler Michele A. , Otali Dennis , Grizzle William , Berry Kristy , Ward Antonio , Babic Ivan , Nurmemmedov Elmar , Zhou Gang , Xing Chengguo , Gorman Greg , Coward Lori , Maxuitenko Yulia , Keeton Adam B. , Piazza Gary A. 
Published: April 2023

Abstract
BACKGROUND: Previous publications have reported that the antineoplastic activity of sulindac occurs by a cyclooxygenase independent mechanism, possibly involving direct inhibition of RAS. Suppression of β-catenin/TCF transcription has also been reported by inhibiting cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) and the activation of cGMP-dependent protein kinase (PKG). Here we characterize a potent and selective non-COX inhibitory sulindac derivative, ADT-030, that inhibits cancer cell growth by blocking RAS and β-catenin signaling.
METHODS AND RESULTS: ADT-030 inhibited the proliferation of lung cancer cells expressing the PDE10A isozyme, while normal airway cells lacking PDE10A displayed reduced sensitivity. ADT-030 inhibited recombinant PDE10 activity at concentrations that inhibit lung cancer cells proliferation. ADT-030 induced cell cycle arrest, apoptosis, and morphological characteristics of autophagy blockage. A cellular thermal stability assay showed that ADT-030 binds both RAS and PDE10 in lysates from cancer cells with nanomolar affinity. Consistent with its PDE10 inhibitory activity, ADT-030 activated PKG and phosphorylated β-catenin on amino acid residues known to induce proteasomal degradation, and reduced levels of the unphosphorylated (oncogenic stabilized) form of β-catenin. Consistent with its ability to directly bind RAS, ADT-030 also inhibited EGF-stimulated MAPK/AKT signaling. Oral administration of ADT-030 inhibited tumor growth in an orthotopic xenograft mouse model of lung cancer, providing a durable survival response with 25% tumor-free mice at dosages having no discernable toxicity. ADT-030 was also highly efficacious in two different chemical-induced mouse models of lung tumorigenesis suppressing the carcinogen-activation of RAS, as well as in multiple mouse subcutaneous tumor models, including highly aggressive models of metastasis.
CONCLUSIONS: These results support further development of ADT-030, a novel inhibitor of RAS and β-catenin signaling for the treatment of lung cancer and other RAS driven cancers, including those with co-occurring mutations in the Wnt/β-catenin pathway.
Supported by NIH grants R01 CA238514, R01 CA197147, R01 CA254197.
Citation Format: Veronica Ramirez-Alcantara, Xi Chen, Michele A. Schuler, Dennis Otali, William Grizzle, Kristy Berry, Antonio Ward, Ivan Babic, Elmar Nurmemmedov, Gang Zhou, Chengguo Xing, Greg Gorman, Lori Coward, Yulia Maxuitenko, Adam B. Keeton, Gary A. Piazza. ADT-030, a novel dual-acting RAS and β-catenin inhibitor with robust antitumor activity [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 1633.