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

phytochemicals, the ginsenoside Rh2, paeonol, 4.2. TOPK and chemotherapies for lung cancer
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xanthohumol, glycyrol, and worenine can target TOPK Chemotherapy is still an important part of targeted therapy,
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to inhibit its activity. Multiple treatment options available immunotherapy, or other new treatments for lung cancer,
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for lung cancer nowadays contain TOPK inhibitors. Table 1 and it is a guaranteed salvage therapy after the occurrence
lists the inhibitors that are effective against lung cancer. of resistance to other therapies. It has been reported that
4.1. TOPK and targeted therapies for lung cancer TOPK regulates paclitaxel-induced cancer cell death
and inhibits paclitaxel-induced autophagy in H460 cells
Gefitinib was the first targeted drug for lung cancer approved by inhibiting p53. The TOPK inhibitor OTS514 could
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by the FDA for the treatment of NSCLC in 2003. Subsequently, enhance the anticancer effect of fluorouracil (5-FU),
other driver gene alterations for lung cancer, including ALK and the combination of 5-FU, OTS514 and the KRAS
rearrangement, RET rearrangement, ROS1 gene fusion, G12C inhibitor AMG510 showed synergistic antitumor
neurotrophic tyrosine receptor kinase 1/2/3 gene fusion, effects. Therefore, the inhibition of TOPK combined with
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BRAF (v-Raf sarcoma viral oncogene homolog B) V600E chemotherapy presents an effective strategy for treating
mutation, HER2 mutation, KRAS G12C mutation, and MET lung cancer.
exon 14 skipping were also identified and discovered. After
proving that these genetic alterations were therapeutic targets, 4.3. TOPK and radiotherapy for lung cancer
corresponding targeted drugs were subsequently developed Approximately 60–70% of lung cancer patients require
as the first-line treatment for patients with advanced NSCLC, radiotherapy at various stages of the disease. For patients
greatly improving the prognosis of these patients. 49,50 At with locally advanced NSCLC, thoracic radiotherapy should
present, there are more than 20 targeted drugs approved by be administered as soon as possible, and simultaneous
the FDA for the first-line clinical treatment of lung cancer. radiochemotherapy followed by immunotherapy is the
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Targeted drugs have greatly improved outcomes for advanced preferred treatment. It has been shown that the tumor-
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NSCLC patients carrying the driver gene alterations. 49 suppressive E3 ubiquitin ligase CHIP could inhibit the
On the one hand, TOPK — a protein kinase — is a TOPK-ERK pathway, and subsequently inhibit the stem
promising drug target. The small molecule compound cell properties and induce radioresistance of NSCLC cells,
inhibitors OTS514 and OTS964 have been proven to providing a promising therapeutic approach for enhancing
inhibit the growth of lung cancer cells by targeting the efficacy of radiotherapy. In lung cancer xenograft
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TOPK. Three traditional Chinese medicine monomer models, TOPK inhibition with OTS964 was shown to
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compounds (baicalin, glycerol, and xanthohumol) can also potentiate fractionated radiotherapy in vivo. Therefore,
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effectively decrease TOPK activity and inhibit lung cancer the inhibition of TOPK can improve the sensitivity of lung
growth both in vivo and in vitro. On the other hand, cancer cells to radiotherapy.
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TOPK inhibitors combined with other targeted drugs can
also enhance sensitivity to targeted drugs and delay the 4.4. TOPK and immunotherapy for lung cancer
development of drug resistance. Xiao et al. reported that Immunotherapy for tumors can be divided into four
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the TOPK inhibitor pantoprazole combined with celecoxib categories: Immune checkpoint inhibitors (PD-1/L1),
and gefitinib led to apoptosis in gefitinib-resistant lung cellular immune cell therapy (CAR-T), tumor vaccines, and
cancer cells and inhibited tumor growth. HI-032 (another nonspecific immunomodulators. Through the analysis
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TOPK inhibitor) in combination with alectinib (a first-line of lung cancer microarray data in the GEO database and
targeted drug for patients with ALK-positive lung cancer) weighted gene co-expression network analysis, TOPK
may be a viable treatment approach for increasing patient was identified as an immune cell infiltration (ICI)-related
sensitivity to targeted therapy. In addition, a recent report hub gene. It is a potential lung cancer-specific marker and
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showed that TOPK transcription can be promoted by UPF1, immunotherapy target and thus, more in-depth studies are
which can subsequently block its anticancer function by warranted. 58
phosphorylating FOXO1 protein in lung cancer cells. The Another study suggested that TOPK is a promising
protein phosphorylation level of FOXO1 decreased in a prognostic marker for immune escape in patients with LUAD.
dose-dependent manner when the kinase activity of TOPK Across bioinformatics analysis, the researchers found that
was inhibited by OTS514. Thus, the UPF1-TOPK-FOXO1 patients with overexpression of TOPK tended to have an
axis may be a potential therapeutic target for lung cancer. 52 immune rejection phenotype, accompanied by an elevated
Taken together, TOPK inhibitors emerge as a class of level of antitumor ICI. Moreover, immune infiltration analysis
targeted therapies for lung cancer and are expected to revealed that the immune escape triggered by the highly
overcome drug resistance. expressed TOPK group might be related to antigen presentation

Volume 3 Issue 2 (2024) 5 doi: 10.36922/gpd.3062