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Gene & Protein in Disease TOPK: Target for lung cancer treatment

indicated that TOPK is one of the most valuable tumor stem cells (CSCs) by inhibiting forkhead box protein
markers, and upregulation of TOPK expression is M1 (FOXM1) activity, thereby exerting greater cytotoxic
demonstrated to be correlated with tumor diagnosis and effects on pulmonary spheroid CSC-like SCLC cells.
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unfavorable prognosis. 11,12 Moreover, TOPK expression was found to be upregulated
Lung cancer is known to cause the highest mortality in NSCLC patients with KRAS mutations. TOPK promoted
among all tumors, and it is also one of the most important the growth and proliferation of A549 cells bearing KRAS
factors leading to the increase in the global cancer burden. G12C mutations by activating the MAPK/ERK signaling
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Surgery, radiotherapy, and drug therapy are the standard pathway. Aside from these, TOPK can also promote the
clinical treatments for lung cancer. During the past few activation of NF-κB signaling in A549 cells carrying KRAS
years, there has been a remarkable advancement in targeted G12C mutations by promoting the phosphorylation of
therapies and immunotherapies, which effectively improve TAK1. 19
patient survival rates. 14 Additionally, TOPK is related to the metastasis of
Here, we summarize the roles and mechanisms of TOPK lung cancer cells. Shih et al. demonstrated that TOPK
in lung cancer and analyze the efficacy of TOPK inhibitors promoted the invasion and migration of lung cancer cells
in various therapeutic treatments for lung cancer. Existing by inhibiting the expression of PTEN, thus alleviating
findings have substantiated TOPK as a valuable target for the negative regulatory effect of PTEN on the PI3K/
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the treatment of lung cancer; therefore, further research Akt signaling pathway. Moreover, hypoxia-inducible
efforts to develop specific inhibitors for comprehensive factor-1α (HIF-1α) can effectively activate and promote
lung cancer therapies are warranted. epithelial-mesenchymal transition under hypoxic
conditions. Another study showed that TOPK could
2. The role of TOPK in lung cancer upregulate HIF-1α levels through hypoxic signaling, thus
promoting the expression of Snail, which led to epithelial-
TOPK is considered a diagnostic/prognostic marker and mesenchymal transition in NSCLC cells. As a novel hypoxia
therapeutic target for lung cancer. As shown in Figure 1, signal regulator, TOPK plays a key role in the migration of
the expression of TOPK was significantly greater in NSCLC cells. 21
both lung adenocarcinoma (LUAD) and lung squamous
cell carcinoma (LUSC) tissues than in normal tissues, These studies showed that TOPK could promote the
according to The Cancer Genome Atlas database (http:// tumorigenesis and progression of lung cancer through
gepia.cancer-pku.cn/; accessed on October 25, 2023). High multiple pathways and could be a potential therapeutic
expression of TOPK promotes tumorigenesis, progression, target for lung cancer.
and drug resistance of lung cancer.
2.2. TOPK promotes drug resistance in lung cancer
2.1. TOPK promotes the tumorigenesis and Drug resistance poses a huge challenge in the treatment
progression of lung cancer of lung cancer. Many researchers have found that TOPK
TOPK is a MAPK-like protein kinase that is known is an important molecule leading to drug resistance in
to be involved in tumorigenesis, and its expression is lung cancer. TOPK is substantially expressed in NSCLC
closely related to the malignant transformation of cells cells that are resistant to epidermal growth factor receptor
and the malignant potential of tumor cells. According to (EGFR)-tyrosine kinase inhibitors (TKIs). It has also
reports, TOPK overexpression actuates JB6 epidermal been demonstrated that TOPK can phosphorylate c-Jun
cell transformation and proliferation both in vitro and and subsequently activate CCND1 and CDC2 due to the
in vivo. 15,16 Consistent with these results, in lung cancer cell resistance of lung cancer cells to EGFR-TKIs. Silencing
lines, TOPK knockdown leads to tumor growth inhibition, TOPK can enhance the sensitivity of EGFR-TKI-resistant
which may help with improving the treatment efficacy lung cancer cells to gefitinib. Furthermore, our previous
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and long-term survival rate of lung cancer patients. Our study revealed high expression of TOPK in NSCLC cells
previous study revealed that TOPK was highly expressed with MET amplification-induced resistance to gefitinib.
in anaplastic lymphoma kinase (ALK)-positive non-small As an upstream molecule, MET regulates the activity of
cell lung cancer (NSCLC) and that the inhibition of TOPK TOPK. The COX2-TXA2 signaling pathway regulates
attenuated cell growth and promoted cell apoptosis. In MET through AP-1, which is then phosphorylated at Tyr74
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addition; inhibiting TOPK could also effectively cause cell to activate TOPK, leading to NSCLC resistance. Another
morphological changes and inhibit the proliferation and study showed that the combination of three U.S. Food and
survival of small cell lung cancer (SCLC) cells. The TOPK Drug Administration (FDA)-approved drugs (celecoxib,
inhibitor OTS514 suppressed the stemness of cancer pantoprazole, and gefitinib) promoted apoptosis in

Volume 3 Issue 2 (2024) 2 doi: 10.36922/gpd.3062