The overall survival rates for lung cancer remain unsatisfactorily low, even for patients with biomarkers for which target therapies or immunotherapies are recommended. Better identification of at‐risk patients is needed to achieve more effective personalized treatment. Here, we derived a risk‐stratifying gene signature consisting of five genes that had the greatest differential expression by stage from lung adenocarcinoma (LUAD) transcriptomes. The new gene signature enabled survival prognosis for multiple LUAD datasets from different platforms of transcriptomics and risk stratification for patients with and without a mutation in TP53 or EGFR, with high and low levels of PD‐L1, and with and without adjuvant chemotherapy treatment. Using these evaluations, it was also shown to be more robust compared to several other gene signatures. Functional analysis of the five genes and their protein‐ protein interaction partners indicated that they are functionally enriched in cell cycle, endocytosis, and EGFR regulation, which are biological processes associated with lung cancer and drug resistance. Extensive discussions on related experimental studies suggest that the five genes are novel and sensible targets for developing new drugs and/or tackling drug resistance problems for LUAD.