Deciphering the prognostic signature of nonsmall cell lung cancer using cisplatin resistance and circulating tumor cell-related gene analysis.

Abstract

This study aimed to develop a prognostic prediction model for nonsmall cell lung cancer (NSCLC) based on cisplatin resistance and circulating tumor cell (CTC)-related genes and to explore the molecular mechanisms of key genes. After downloading and preprocessing data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, a prognostic signature was developed using least absolute shrinkage and selection operator (LASSO) regression analysis. Patients were categorized into low-risk (LR) and high-risk (HR) groups based on their risk score (RS), and differences in survival, immune infiltration, and immunotherapy/chemotherapy responses were compared. A nomogram was established for clinical application, followed by identification of molecular subtypes. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to verify the expression of key genes in the A549 and A549/DDP cell lines. Finally, we explored the molecular mechanisms by which inhibition of FAM83A reversed cisplatin resistance. Using LASSO regression, a prognostic signature with eight genes was developed; the survival rate of patients in the HR group was significantly lower than that of patients in the LR group (all P < 0.05). The RS was an independent risk factor for NSCLC and stably predicted the prognosis (P < 0.05). The immune infiltration levels of LR and HR patients were significantly different, and the model could effectively predict the response to drugs or immunotherapy (all P < 0.05). Subsequently, subtype clustering divided the patients into two groups to assist in identifying heterogeneity between patients with different risks. Finally, qRT-PCR confirmed that these genes were aberrantly expressed in A549 cells and were closely associated with cisplatin resistance (all P < 0.05). Notably, FAM83A overexpression promoted the proliferation and invasion and inhibited the apoptosis of A549 cells (all P < 0.05). Low FAM83A expression reversed cisplatin resistance in lung cancer cells (P < 0.05). The eight-gene model constructed in this study can predict the prognosis of patients with NSCLC and guide personalized treatment. In addition, targeted inhibition of FAM83A expression can reverse cisplatin resistance, potentially enhancing the efficacy of chemotherapy in combination with immunotherapy, thereby providing a novel strategy for clinical practice.