Abstract PO-045: Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer

Abstract

Abstract Interleukin-1 Receptor Accessory Protein (IL1RAP) is a surface molecule that mediates activation of pro-inflammatory IL-1 associated signaling pathways. It is overexpressed in myeloid leukemias and is associated with worse prognosis. We aimed to evaluate IL1RAP as a target for therapy in pancreatic adenocarcinoma (PDAC). Immunohistochemistry demonstrated overexpression of IL1RAP in PDAC specimens from K-Ras/p53/Cre (KPC) mice when compared to controls. Evaluation of human PDAC tissue microarrays containing 262 samples also revealed overexpression of IL1RAP in 81% of the samples. Single cell RNA-Seq analysis of human primary pre-neoplastic lesions and frank adenocarcinoma specimens indicated that overexpression occurs on malignant EPCAM positive cells during carcinogenesis. IL1RAP knockdown via siRNA on the A6L PDAC cell line significantly reduced cell viability, invasiveness, and ability to form colonies. IL1RAP knockdown cells showed significant arrest in the G1/G0 phase of the cell cycle on flow cytometry and showed reduced phospho-ERK proliferative signaling on Western blot. RNA sequencing of IL1RAP knockdown cells indicated downregulation of several groups of genes involved in cell cycle progression, including CDK1 and TOP2A, whose reduced expression was confirmed on Western blot. Inhibition of the downstream signaling molecule IRAK4 (interleukin-1 receptor-associated kinase 4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in significantly reduced growth in pancreatic cancer cell lines and reduced proliferative phospho-ERK signaling on Western blot. Preliminary in vivo data in NSG mice showed a reduction in tumor size with oral treatments of these two IRAK4 inhibitors. Overall, our studies indicate IL1RAP is overexpressed in PDAC, and reducing IL1RAP and inhibiting downstream IRAK4 result in lowered tumor proliferation in vitro and in vivo, potentially via cell cycle arrest and reduced proliferative signaling. Citation Format: Yang Zhang, Xiaoyi Chen, Shanisha Gordon-Mitchell, Kith Pradhan, Gaurav Choudhary, Tushar D. Bhagat, Beamon Agarwal, Ulrich Steidl, Anirban Maitra, Amit Verma. Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-045.