Abstract 379: Genomic profiling of the tumors harboring activating epidermal growth factor receptor mutations
Authors: Jingrui Jiang, Meaghan Russell, Cheryl Eifert, Angeliki Pantazi, Ruobai Sun, Stephen Lyle, Joerg Heyer, Alexei Protopopov
Journal: Cancer Research (2017)

Abstract Introduction: EGFR is a kinase of the HER/ERBB family and an oncogenic driver, especially for NSCLC, HNSCC and CRC. EGFR targeted therapies have been successfully used for treating cancer patients harboring activating EGFR mutations. However a main challenge is acquired drug resistance due to mutations or alternative signaling. While developing next generation drugs is a promising strategy, targeting other alternatives is also an attractive therapeutic option. The purpose of our study is to investigate the mutational landscape of the tumors harbored activating EGFR mutations and to pinpoint potential strategies for overcoming acquired drug resistance and for combinational therapies. Methods: CancerPlex, a NGS large panel test, which includes targeted, full-gene sequencing of over 400 genes, was applied to analyze a cohort of 2294 patient FFPE samples across majority of solid tumor types. Results: 1, Among 293 (out of 2294, 12.8%) samples harbored EGFR mutations, 86 (86/293, 29.4%) samples harbored actionable EGFR mutations (namely AE group), such as exon 19 deletion and L858R, which includes 84 lung cancer (79 NSCLC), 1 glioblastoma, and 1 urothelial carcinoma. 2, The genes/variants in the AE group are then subjected to further functional analysis and mapped to several pathways/ biological functions. Our results show that the mutational landscape of activating mutant EGFRs covers most main signaling pathways and biological processes with several features: a), Receptors at different classes, including PKHD1, ROS1, and ERBB2, and genes involving in genome and epigenome stabilities, including ARID1A,, KMT2D, and XPC, have the highest mutation rate in the context of activating EGFR mutations. b), PI3K/AKT/mTOR and Ras-Raf-MEK are two main pathways transducing ligand activated EGFR signals. Our results show that the mutant variants in the PI3K-AKT-mTOR pathway are almost 50% more than those in Ras-Raf-MEK pathway, suggesting that activating mutant EGFRs might preferentially rely on effectors in the PI3K pathway, such as PIK3CA and RICTOR, to transduce oncogenic signals. Of note, no KRAS mutation is found in the AE group. c), As expected, mutations are also found in the TP53/apoptosis and Rb/cell cycle pathways with higher variant number in the TP53/apoptosis axis. d) Strikingly, the number of mutant variants in the Wnt/beta-catenin pathway tops that in the PI3K and TP53 pathways. Several recent publications demonstrated that the Wnt/beta-catenin pathway is abnormally activated in NSCLC and may be a main mechanism of the drug resistance. Our finding that the genes in the Wnt/beta-catenin pathway, including APC, AXIN2, RNF43, and BCL9, are mutated to a great extent in the context of activating EGFR mutations supports the notion that targeting the Wnt/beta-catenin pathway, in combination with EGFR targeted therapies, is a promising therapeutic strategy for the treatment and overcoming drug resistance of EGFR-driven tumors. Citation Format: Jingrui Jiang, Meaghan Russell, Cheryl Eifert, Angeliki Pantazi, Ruobai Sun, Stephen Lyle, Joerg Heyer, Alexei Protopopov. Genomic profiling of the tumors harboring activating epidermal growth factor receptor mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 379. doi:10.1158/1538-7445.AM2017-379