KRASG12C mutation-induced TOPK overexpression contributes to tumour progression in non-small cell lung cancer

by Selleckchem | Sep 30 2023

KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.

Comments:

Your research findings indicate that the KRAS-TOPK axis plays a significant role in the progression of non-small cell lung cancer (NSCLC), particularly in cases with the KRASG12C mutation. Here's a breakdown of the key findings and implications of your study:

1. KRAS mutation: KRAS is the most common genetic mutation found in NSCLC, particularly in lung adenocarcinoma. However, the specific mechanisms by which KRAS mutations drive carcinogenesis in NSCLC have not been fully elucidated.

2. Association with TOPK: Your research identified an association between the KRASG12C mutation and the upregulation of T-LAK cell-originated protein kinase (TOPK). TOPK is a well-known serine/threonine MAPK-like protein kinase that has been implicated in tumorigenesis.

3. Impact on malignant phenotype: The overexpression of TOPK was found to significantly promote the malignant phenotype of A549 cells, indicating its role in driving tumor progression. Conversely, silencing TOPK impaired the malignant phenotype, suggesting its potential as a therapeutic target.

4. Regulation by MAPK/ERK signaling and Elk1: Your study demonstrated that TOPK levels are regulated by the MAPK/ERK signaling pathway and the transcription factor Elk1. This finding provides insights into the upstream regulatory mechanisms controlling TOPK expression.

5. Activation of NF-κB signaling: TOPK was found to promote the activation of NF-κB signaling in A549 cells with the KRASG12C mutation by facilitating the phosphorylation of TAK1. This highlights a potential mechanism by which TOPK contributes to the progression of NSCLC.

6. Therapeutic implications: In an in vivo tumorigenesis model, the administration of the TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, a commonly used chemotherapeutic agent. Additionally, combining the TOPK inhibitor OTS514 with the KRASG12C inhibitor AMG510 showed a synergistic anti-tumor effect. These findings suggest that targeting the KRAS-TOPK axis could enhance the efficacy of existing chemotherapeutics in treating NSCLC.

In summary, your research demonstrates that the KRAS-TOPK axis plays a crucial role in the progression of NSCLC, particularly in cases with the KRASG12C mutation. The findings provide insights into the underlying mechanisms and suggest that targeting this axis could potentially improve the efficacy of existing chemotherapeutic agents in treating NSCLC.