Abstract A049: Collagen-driven kinome reprogramming reveals unique, actionable DDR1-signaling dependencies in pancreatic cancer cells

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Abstract Introduction: Pancreatic ductal adenocarcinoma (PDA) is the 3rd most common cause of cancer death in the United States, with a 5-year survival rate of only 13%, in part due to late detection and metastatic dissemination at early stages of progression. Most PDA tumors exhibit a dense fibro-inflammatory stroma consisting of fibroblasts, immune cells, and a dense collagen-rich extracellular matrix (ECM) that regulate disease progression. How distinct collagens (COLs) influence PDA progression remains unclear. COLs signal via specific cell surface receptors, of which the Discoidin Domain Receptors (DDRs) constitute a unique family of collagen-binding receptor tyrosine kinases (RTKs). DDR1 is expressed by PDA cancer cells, while DDR2 is expressed by mesenchymal cells. DDR1 is activated by both basement membrane COL (e.g. COL4) and fibrillar COLs (e.g. COLs 1, 2, 11). Compared to most RTKs, relatively little is understood about differential ligand activation and signaling downstream of DDRs. Our working hypothesis is that switches in ECM collagen composition over the course of PDA progression induce changes in DDR1-intracellular signaling cascades, which may reveal unexplored therapeutic susceptibilities to target and eliminate PDA cancer cells. Methods and Recent Advances: Using genetically engineered mouse models of PDA, we previously found that genetic ablation of Ddr1 impedes tumor progression, blocking the transition from well-differentiated to poorly-differentiated adenocarcinoma and, as a result, metastasis. Moreover, we showed that xenografts of DDR1-expressing human PDA cell lines display enhanced tumor growth exclusively when implanted within a COL1 scaffold. Leveraging an innovative high-throughput kinase-activity mapping (HT-KAM) platform and kinase network resource database (PhosphoAtlas), we started investigating mechanisms of differential activation of DDR1 by distinct COLs, including COL1 and COL11, which is an understudied fibrillar collagen that is prominent in the stroma of late-stage, metastatic PDA. New, Unpublished Findings: Using several PDA cell line models with or without DDR1 expression, our results indicate that DDR1 activates two distinct signaling networks: (1) a conserved, coordinated response that is modestly activated by COL1 but is hyperactivated by COL11 (e.g., ERBB, AKT, MEK/ERK, SRC), and (2) a unique set of phospho-signaling nodes that are only induced by COL11 –and not COL1 (e.g., specific RTKs and PKCs). Several of these kinases are associated with cancer cell proliferation and survival, as well as EMT induction, in part illuminating the malignancy-promoting effects of DDR1 in late-stage PDA in response to changes in COL composition. Conclusion: Differential activation of DDR1 represents a new paradigm on how distinct fibrillar COLs within the TME may drive PDA cell signaling. We are actively exploring how distinct COLs differentially regulate PDA tumor growth and metastatic behavior via DDR1, and how specific kinase-targeting interventions may prevent malignant phenotypes or induce tumor cell death. Citation Format: Anjum Sohail, Yeonjoo Hwang, Denise P Munoz, Yoshihiro Ishikawa, Rafael Fridman, Howard Crawford, Jean-Philippe Coppe. Collagen-driven kinome reprogramming reveals unique, actionable DDR1-signaling dependencies in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A049.