Abstract 5004: DDR-targeting small molecule inhibitor as a novel therapeutic for treating pancreatic ductal adenocarcinoma

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the second most significant cause of cancer-related mortality, with a 5-year survival rate of just 11%. PDACs are one of the most difficult to treat cancers, mainly because of the desmoplastic tumor microenvironment enriched with tumor-supportive extracellular matrix (ECM) and stromal cells. Unfortunately, the efficacies of current pancreatic cancer therapies are limited partly by stroma-mediated drug resistance. We reason that Discoidin Domain Receptors, which belong to the receptor tyrosine kinase family and bind to fibrillar collagens present in the ECM, may be a critical promoter of PDAC growth and progression. Though several drugs targeting DDR proteins have been developed, no inhibitors specific to DDR proteins have been developed. Moreover, those drugs have not been approved for treating PDACs. Methods. A high throughput screen using small molecule inhibitors was performed to identify bonafide inhibitors of DDR proteins. Structural and reported-based essays were done to determine the specificity. Functional assays were performed to test the potency of the candidate inhibitors. Mechanistic studies were done using RNA-seq, real-time PCR, and western blot. Results: Using an unbiased screening approach, we identified inhibitors that specifically target DDR proteins. Our studies revealed that small molecule inhibitors blocked the short and long-term viability as well as migration/invasion of PDAC cells. In addition, they induced apoptosis and halted the cell cycle at the G1-S checkpoint. Mechanistic studies revealed that the pro-growth signaling cascade was significantly inhibited. Conclusions: Our results showing specific DDR inhibitors blocking the growth and progression of PDAC cells without affecting the viability of normal cells suggest that these inhibitors may serve as a safe and potent regimen for treating pancreatic cancers. Citation Format: Trong Phat Do, Sajid Khan, Daohong Zhou, Matthew Hart, Stanton McHardy, Manjeet Rao. DDR-targeting small molecule inhibitor as a novel therapeutic for treating pancreatic ductal adenocarcinoma. [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 5004.