Genomic Profiling on an Unselected Solid Tumor Population Reveals a Highly Mutated Wnt/β-Catenin Pathway Associated with Oncogenic EGFR Mutations

Abstract

Oncogenic epidermal growth factor receptors (EGFRs) can recruit key effectors in diverse cellular processes to propagate oncogenic signals. Targeted and combinational therapeutic strategies have been successfully applied for treating EGFR-driven cancers. However, a main challenge in EGFR therapies is drug resistance due to mutations, oncogenic shift, alternative signaling, and other potential mechanisms. To further understand the genetic alterations associated with oncogenic EGFRs and to provide further insight into optimal and personalized therapeutic strategies, we applied a proprietary comprehensive next-generation sequencing (NGS)-based assay of 435 genes to systematically study the genomic profiles of 1565 unselected solid cancer patient samples. We found that activating EGFR mutations were predominantly detected in lung cancer, particularly in non-small cell lung cancer (NSCLC). The mutational landscape of EGFR-driven tumors covered most key signaling pathways and biological processes. Strikingly, the Wnt/β-catenin pathway was highly mutated (48 variants detected in 46% of the EGFR-driven tumors), and its variant number topped that in the TP53/apoptosis and PI3K-AKT-mTOR pathways. Furthermore, an analysis of mutation distribution revealed a differential association pattern of gene mutations between EGFR exon 19del and EGFR L858R. Our results confirm the aggressive nature of the oncogenic EGFR-driven tumors and reassure that a combinational strategy should have advantages over an EGFR-targeted monotherapy and holds great promise for overcoming drug resistance.

The expression of circulating miR-504 in plasma is associated with EGFR mutation status in non-small-cell lung carcinoma patients

“…β-catenin levels were increased in NSCLC cells with oncogenic EGFR mutations, as well as in gefitinib-resistant cells, and inhibition of the Wnt/β-catenin pathway re-sensitised cells to EGFR inhibitors and increased their efficacy in these tumours [53–55]. Recently, Jiang et al reported that EGFR -activating mutations in NSCLC co-occurred with mutations in genes participating in most key signalling pathways and biological processes, including receptors of different classes, key regulators involved in genome and epigenome stability, the PI3K–AKT–mTOR pathway, and the TP53/apoptosis pathway [56]. In the study by Jiang et al, many of the Wnt/β-catenin pathway-related genes linked to oncogenic EGFRs were mutated, and there was more variation in the Wnt/β-catenin pathway than in the TP53/apoptosis and PI3K–AKT–mTOR pathways.…”

Survival analysis of genome-wide profiles coupled with Connectivity Map database mining to identify potential therapeutic targets for cholangiocarcinoma

“…The Wnt signaling pathway is essential for the survival of stem cells and the maintenance of the regenerative ability of tissues ( 20 ). The basic role of the Wnt/β-catenin pathway in development requires regulatory control at multiple levels, and a deficiency at any level may lead to tumor formation ( 21 ). Previous studies have demonstrated that the proliferation, invasion and epithelial-mesenchymal transition of CCA cells are associated with Wnt/β-catenin signaling ( 22 , 23 ).…”

Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach

“…The deregulations involve hijacking stem cell self-renewal and its multi-lineage differentiation ability. Subsequently, activation of oncogenes leads to adenocarcinoma development [6–9]. Patients whose tumors are driven by EGFR classical mutations have been shown to respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including Gefitinib, Erlotinib, Afatinib and Osimertinib [10–13].…”