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

Abstract

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.

1. Introduction

Lung squamous cell carcinoma (LUSC) is a type of non-small cell lung cancer, which accounts for approximately 20%–30% of lung cancer cases [1]. At present, surgery, immunotherapy, radiotherapy, and chemotherapy are still the main treatments for LUSC patients. The treatment methods are relatively limited, and resistance to radiotherapy and chemotherapy often occurs; immunotherapy is also prone to adverse reactions or failure [2]. With the emergence of targeted drugs, the therapeutic effect on lung adenocarcinoma (LUAD) has improved, and the survival period of patients is continuously prolonged. However, unlike LUAD patients, LUSC patients have not yet benefited from targeted therapy. Common driver mutations in LUAD, such as those in EGFR and KRAS, rarely occur in LUSC. The mutation sites discovered in LUSC, such as those in SOX2, FGFR1, and NSD3, have not yet been successfully identified as targeted drugs [3]. Therefore, new LUSC therapeutic targets still need to be identified.

SRC is a nonreceptor tyrosine kinase protein that is commonly expressed in normal tissues. SRC has been identified as an important oncoprotein that can promote cancer progression, invasion, metastasis and drug resistance in various cancers, including colorectal cancer, breast cancer, pancreatic cancer, and gastric cancer [4–6]. SRC has been studied in NSCLC, especially LUAD. Onodera et al. [7] demonstrated that the simultaneous inhibition of SRC and Rho/ROCK had a synergistic effect on the growth of NSCLC cells. SRC interacts with cell surface growth factor receptors and intracellular signaling pathways to maintain cell survival in NSCLC [4]. However, there is still a lack of evidence to determine whether SRC is involved in the occurrence and development of LUSC.

T-LAK cell-derived protein kinase (TOPK), also known as PDZ binding kinase (PBK), is a serine threonine protein kinase belonging to the MAPK kinase family. TOPK is involved in inflammatory reactions and is also a procancer factor. Overexpression of TOPK is a poor prognostic factor in LUAD patients and is closely associated with P53 mutations [8,9]. KRASG12C mutation-induced TOPK overexpression promotes NSCLC tumor progression, mediating hypoxia-induced epithelial mesenchymal transition and NSCLC cell invasion through the HIF-1 α/snail axis [10,11]. In addition, our previous research revealed that TOPK promoted lung cancer resistance to EGFR inhibitors by phosphorylating c-Jun and that inhibiting the COX2/MET/TOPK signaling axis weakened NSCLC cell resistance to EGFR inhibitors [12,13].