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

and infiltration by dendritic cells and CD8 T cells. However, mitosis by attenuating its activity. The inhibition of TOPK
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the immune spectrum of patients was poorly characterized, does not undermine the function of non-proliferative cells
and the role of immunosuppressive cells in the tumor and has lesser off-target effects. Therefore, TOPK would
microenvironment remains unclear. An experimental study serve as an ideal target. However, the three-dimensional
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showed that inhibition of TOPK significantly enhanced CD8 structure of TOPK remains uncharacterized, and the
T cell infiltration and activated CD8 T cells and enhanced the development of TOPK inhibitors is progressing slowly.
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effect of anti-PD-L1 therapy, thereby synergistically enhancing The efficacy of inhibitors such as OTS964 in lung cancer
the immune response against renal cell carcinoma. 59 has yet to be confirmed in preclinical and clinical studies.
In addition, mRNA vaccines are a novel immunotherapy Overall, TOPK is a noteworthy kinase for targeted therapy
strategy for lung cancer. Across antigen-presenting cell- in lung cancer, but in-depth research is required to explore
associated cancer-associated antigen screening and its inhibitors.
prognosis analysis, Zhou et al. identified TOPK as a In addition, TOPK is regarded as a promising
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potential candidate antigen for mRNA vaccines. These immunotherapy target for lung cancer. Because of its highly
predictive analyses need to be further verified in lung specific expression in normal testes and tumors, TOPK
cancer in a well-designed experimental scheme. has also been identified as a cancer/testis antigen (CTA)
and is included in the CT database (http://www.cta.lncc.
5. Conclusions and perspectives br/gene_annotations.html). Lung cancer vaccines and
The discovery of EGFR, ALK, MET, and other targets other immunotherapies target CTAs because of their high
has profoundly prompted the development of targeted antigenicity and tumor selectivity. Vaccines, chimeric antigen
drugs, which improve the prognosis of advanced receptor-modified T cells (CAR-T cells), and small molecule
NSCLC patients carrying the corresponding driver gene inhibitors targeting CTAs have been used in preclinical
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alterations. 49,51 Unfortunately, only approximately 25% and early-stage clinical trials for lung cancer treatment.
of patients can benefit from targeted therapy. There TOPK has also been claimed as an immunotherapy target
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are two major challenges in the development of targeted and a potential candidate antigen for mRNA vaccines.
therapies for lung cancer: (1) The known targets and An experimental study showed that inhibition of TOPK
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drugs available are limited. Thirty-one percent of the significantly enhanced CD8 T-cell infiltration activated
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unknown tumor driver genes have potential therapeutic CD8 T cells and potentiated the effect of anti-PD-L1 therapy,
targets for lung cancer, which is worthy of further study thereby synergistically strengthening the immune response
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and (2) drug resistance hinders targeted therapy. The against renal cell carcinoma. Therefore, the role of TOPK in
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molecular mechanism of resistance is related not only lung cancer immunotherapy is worthy of further exploration.
to genetic changes, such as site mutations, deletions, Acknowledgments
and gene amplifications but also to the activation of
bypass pathways or phenotypic changes in tumor cells. None.
The mechanism of drug resistance in more than 10% Funding
of drug-resistant patients remains unclear. Overall,
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it is necessary to explore novel targets for lung cancer This work was supported by the National Natural Science
treatment and develop corresponding inhibitors for Foundation of China (Grant no. 82260528, 8190284), and
targeted therapy. Of note, protein kinases are the main the International Cooperation Projects of Henan Province
targets of NSCLC-targeted drugs. The targets of the first- (Grant no. 232102521030).
line targeted drugs for advanced NSCLC approved by the
FDA are all tumor-associated protein kinases. 63 Conflict of interest
Similar to classical targets such as ALK and MET, The authors declare that they have no competing interests.
TOPK is involved in a wide variety of biological functions Author contributions
in lung cancer, such as tumorigenesis, progression,
metastasis, and drug resistance, through the activation Conceptualization: Juanjuan Xiao, Feng Zhu, Yijie Zhang
of diverse downstream signaling pathways. Based on the Writing – original draft: Wenbo Liu, Juanjuan Xiao
research by Illuminating the Druggable Genome (IDG), Writing – review & editing: Feng Zhu, Qiuhong Duan,
initiated by the United States National Institutes of Health, Yafang Li, Shuang Zhao
TOPK could bind to small drug-like molecules with high
affinity and specificity. Thus, it has the potential to be a Ethics approval and consent to participate
“druggable” kinase. TOPK, an oncokinase that inhibits Not applicable.
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Volume 3 Issue 2 (2024) 7 doi: 10.36922/gpd.3062