Abstract 2904: Small molecule inhibitor targeting DDR represents a novel therapeutic strategy for the treatment of pancreatic ductal adenocarcinoma (PDAC)

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is ranked as the second leading cause of cancer-related mortality with a 5-year survival rate of merely 12%. The complexity of PDAC lies in its intrinsic resistance to treatment, attributable to the desmoplastic tumor microenvironment, characterized by an abundance of tumor-promoting extracellular matrix (ECM) and stromal cells. We hypothesize that Discoidin Domain Receptors (DDR), members of the receptor tyrosine kinase family known for their affinity to fibrillar collagens within the ECM, play an important role in promoting PDAC growth and progression. While several drugs targeting DDR proteins have been developed, no inhibitors to DDR proteins are specific or approved for PDAC treatment, thus necessitating the development of novel therapeutic interventions. Methods. A comprehensive high-throughput screening approach employing small molecule inhibitors was executed to identify authentic inhibitors targeting DDR. Subsequently, a rigorous evaluation of specificity of these small molecules was conducted through structural activity relationship (SAR) analyses and reference-based assessments. The efficacy of candidate inhibitors was assessed through functional assays, while mechanistic insights were gleaned using a multifaceted approach, including RNA-seq, real-time PCR, western blot analysis, in vivo experimentation, and Phospho-Receptor Tyrosine Kinase (RTK) profiling to discern any unintended off-target effects. Results: Using an unbiased screening approach, we identified 13 inhibitors that specifically target DDR. SAR studies and cellular thermal shift assay validated CIDD-0108633 (8633) as a bona fide DDR2 inhibitor. Functional assays and RNA-seq analyses demonstrated 8633's capacity to inhibit PDAC growth, metastatic potential, and expression of DNA replication, cell-cycle, and DNA damage repair genes. Combination therapy of 8633 with gemcitabine synergistically reduced PDAC cell viability and metastatic potential. Mechanistic studies revealed the role of ABC transporters in mediating gemcitabine resistance. RTK profiling shows moderate kinase selectivity. In vivo studies affirmed its antitumor effects. Conclusions: The results indicate that the selective inhibition of DDR with small molecule inhibitors suppresses PDAC cell growth and progression, implying that DDR inhibitors have the potential to be developed as safe and efficacious therapeutics for the treatment of pancreatic cancers. Citation Format: Trong Phat Do, Jack Prochnau, Prabhakar Pitta Venkata, Sajid Khan, Santosh Timilsina, Deepika Singh, Daisy Medina, Radhika Amaradhi, Daohong Zhou, Matthew Hart, Stanton McHardy, Manjeet Rao. Small molecule inhibitor targeting DDR represents a novel therapeutic strategy for the treatment of pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2904.