Abstract PO-079: Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer

Abstract

Abstract Pancreatic adenocarcinoma (PDAC) remains an extremely lethal disease with few effective therapeutic options. Targeted therapy development has remained largely unsuccessful due to complex tumor heterogeneity and better molecular indicators of response are urgently needed. We have previously identified two distinct molecular tumor subtypes in PDAC, basal-like and classical, which are prognostic and dictate response to chemotherapy. We have also developed a patient derived xenograft (PDX) mouse model that maintains the integrity of patient tumor biology and recapitulates primary tumor subtypes in vivo. Here, we aim to utilize multiplexed kinase inhibitor beads and quantitative mass spectrometry (MIB-MS) to determine baseline kinase expression and adaptive kinome responses to therapy in PDAC PDX tumors. A total of 381 kinases were identified across all samples and tumor specific kinases were isolated by alignment to human peptides. Distinct kinase expression profiles were observed for basal-like and classical tumors. Basal-like tumors showed high expression of kinases involved in receptor tyrosine kinase activity, MAP kinase activity, and clathrin-dependent endocytosis. Classical subtype tumors showed increased expression of kinases involved in metabolism and cytoskeletal regulatory kinases. Differential protein expression was further validated by differential gene expression using RNAseq. MIB profiling of kinome response to EGFR inhibition by erlotinib indicated kinome reprogramming with upregulation of microtubule associated kinases and MAP kinase family members. Overall, these results suggest that basal-like and classical subtype tumors exhibit distinct kinome profiles that present possible subtype specific vulnerabilities to kinase inhibition. Stratifying kinase inhibitor therapies based on tumor subtype could improve response to targeted therapies in PDAC. Citation Format: Yi Xu, Michael East, Ashley Morrison, Gabriela Herrera, Laura Peng, Gary Johnson, Jen Jen Yeh. Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-079.