Predicting Chemo-Radiotherapy Sensitivity With Concordant Survival Benefit in Non-Small Cell Lung Cancer

Background: To identify a computed tomography (CT) derived radiomic signature for the options of concurrent chemo-radiotherapy (CCR) in patients with non-small cell lung cancer (NSCLC). Methods: A total of 226 patients with NSCLC receiving CCR were enrolled from public dataset, and allocated to discovery and validation sets based on patient identification number. Using CT images of 153 patients in the discovery dataset, we pre-selected a list of radiomic features significantly associated with 5-year survival rate and adopted the least absolute shrinkage and selection operator regression to establish a predictive radiomic signature for CCR treatment. We performed transcriptomic analyzes of the signature, and evaluated its association with molecular lesions and immune landscapes in a dataset with matched CT images and transcriptome data. Furthermore, we identified CCR resistant genes positively correlated with resistant scores of radiomic signature and screened essential resistant genes for NSCLC using genome-scale CRIPSR data. Finally, we combined DrugBank and Genomics of Drug Sensitivity in Cancer databases to excavate candidate therapeutic agents for patients with CCR resistance, and validated them using the Connectivity Map dataset. Results: The radiomic signature consisting of nine features was established, and then validated in the dataset of 73 patients receiving CCR log-rank P = 0.0005, which could distinguish patients into resistance and sensitivity groups, respectively, with significantly different 5-year survival rate. Furthermore, the novel proposed radiomic nomogram significantly improved the predictive performance (concordance indexes) of clinicopathological factors. Transcriptomic analyzes linked our signature with important tumor biological processes (e.g. glycolysis/glucoseogenesis, ribosome). Then, we identified 36 essential resistant genes, and constructed a gene-agent network including 10 essential resistant genes and 35 candidate therapeutic agents, and excavated AT-7519 as the therapeutic agent for patients with CCR resistance. The therapeutic efficacy of AT-7519 was validated that significantly more resistant genes were down-regulated induced by AT-7519, and the degree gradually increased with the enhanced doses. Conclusions: This study illustrated that radiomic signature could non-invasively predict therapeutic efficacy of patients with NSCLC receiving CCR, and indicated that patients with CCR resistance might benefit from AT-7519 or CCR treatment combined with AT-7519.