The SRC-TOPK positive feedback loop promotes RB1 phosphorylation and drives the development of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is a common subtype of non-small cell lung cancer, with limited treatment options and poor patient prognosis. Currently, common driver mutations in lung adenocarcinoma rarely occur in LUSC; the mutated genes found in LUSCs lack corresponding targeted drugs. Therefore, it is necessary to discover new therapeutic targets for LUSC and provide patients with more treatment options. By analyzing different databases and tissue microarray immunohistochemistry staining, we firstly find that the expression of SRC/TOPK is elevated and positively correlated in LUSC and that patients with high SRC/TOPK expression have shorter survival time. Changing the expression levels of SRC/TOPK in LUSC cells can affect cell growth and colony formation, as there is a positive feedback loop between SRC and TOPK that regulates the transcription factor RB1, thereby altering the expressions of key factors in some growth-related signaling pathways. These inhibitors can synergistically promote apoptosis and have been validated in vivo. Therefore, the positive feedback loop between SRC and TOPK promotes tumorigenicity by inhibiting RB1 function, and has the potential to become a precise therapeutic target for LUSC, providing new possibilities for targeted therapy.