An EGFR signature predicts cell line and patient sensitivity to multiple tyrosine kinase inhibitors

EGFR is an oncogene with a high frequency of activating mutations in nonsmall cell lung cancer (NSCLC). EGFR inhibitors have been FDA‐approved for NSCLC and have shown efficacy in patients with certain EGFR mutations. However, only 9% to 26% of these patients achieve objective responses. In our study, we developed an EGFR gene signature based on The Cancer Genome Atlas (TCGA) RNA‐seq data of lung adenocarcinoma (LUAD) to direct the preselection of patients for more effective EGFR‐targeted therapy. This signature infers baseline EGFR signaling pathway activity (denoted as EGFR score) in tumor samples, which is associated with tumor sensitivity to EGFR inhibitors and other tyrosine kinase inhibitors (TKIs). EGFR score predicted sensitivity of lung cancer cell lines to Erlotinib, Gefitinib and Sorafenib. Importantly, EGFR score calculated from pretreated samples was associated with patient response to Gefitinib and Sorafenib in lung cancer. Additionally, integration of the EGFR signature with TCGA LUAD data showed that it accurately predicted functional effects of different somatic EGFR mutations, and identified other mutations affecting EGFR pathway activity. Finally, using cancer cell line and clinical trial data, the EGFR score was associated with patient response to TKIs in liver cancer and other cancer types. The EGFR signature provides a useful biomarker that can expand the application of EGFR inhibitors or other TKIs and improve their treatment efficacy through patient stratification. What's new? EGFR is an oncogene with a high frequency of activating mutations in non‐small cell lung cancer (NSCLC). NSCLC patients who have been shown to benefit from treatment with EGFR inhibitors remain a minority, however. This study defined a platform‐independent gene signature that captures EGFR pathway activity by examining the downstream transcriptomic readout. The signature could detect EGFR somatic mutations in lung cancer cell lines and tumor samples and predict patient response to EGFR and other tyrosine kinase inhibitors. This new signature holds the potential to expand the application of EGFR inhibitors and aid physicians in pre‐selecting patients for targeted therapy.