4.5 Article

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

Journal

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 27, Issue 12, Pages 1637-1652

Publisher

WILEY
DOI: 10.1111/jcmm.17640

Keywords

KRAS(G12C); NSCLC; proliferation; TOPK

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KRAS(G12C) mutation is associated with upregulation of T-LAK cell-originated protein kinase (TOPK), which promotes the malignant phenotype of A549 cells with KRAS(G12C) mutation. TOPK level is regulated by MAPK/ERK signalling and the transcription factor Elk1. It also activates the NF-kappa B signalling pathway by facilitating the phosphorylation of TAK1. Targeting the KRAS-TOPK axis synergizes with existing chemotherapeutics in treating NSCLC.
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 KRAS(G12C) 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 KRAS(G12C) 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-kappa B signalling in A549 cells with KRAS(G12C) 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 KRAS(G12C) 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.

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