Screening potential therapeutic drugs for lung adenocarcinoma based on hypoxia and pyrimidine metabolism models

The development of prognostic markers related to hypoxia and metabolism (HM) is of great significance for the treatment and prognosis of lung adenocarcinoma (LUAD) patients.

We use many tumor and metabolism-related data, gene sets, and risk model-building methods. Next, we selected HM pathways with more prognostic relevance (HP) and established an HP-related prognostic model (HPMD). Further, we probed the correlation between HPMD and clinical pathology. The high-expression genes (HPGS) of the high-risk group of HPMD, identified in the CMap dataset (HPGPS), are used to screen for potential drugs that inhibit LUAD. Then, analyze the difference in inhibition of tumor cells between the two small-molecule drugs with the highest negative correlation, using plate cloning, CCK8, and flow cytometry analysis. Meanwhile, HPGPS was used to construct an HP-related risk gene model (HPGPSMD). In contrast, the gene expression comprehensive dataset (GEO) was used to validate the prognostic significance of risk genes (HPGPSS). Finally, the expression changes of small molecule drugs on HPGPSS were validated through polymerase chain reaction and Western blotting.

High hypoxia-pyrimidine metabolism is unfavorable for the prognosis; the HPMD score is closely related to clinical pathological development and prognostic parameters. The CMAP database shows verapamil and apigenin have the highest negative correlation with HPGPS scores. Subsequently, at the same concentration, there was a significant difference in the inhibitory proliferation and anti-apoptotic ability of verapamil and apigenin on tumors. Subsequently, HPGPSS are closely related to hypoxia and pyrimidine metabolism, as well as clinical pathological development and prognosis. Finally, at the same concentration, apigenin has a higher inhibitory effect on the expression of HPGPSS.

HPGPSS is closely related to patient prognosis and tumor development and provides a new approach for screening prognostic diagnostic biomarkers and potential small-molecule drugs for the treatment of LUAD.