The Inhibition of Wnt Restrain KRASG12V-Driven Metastasis in Non-Small-Cell Lung Cancer

The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRAS(G12V)/KRAS(G12D) mutations and inhibited the KRAS(G12V) mediated metastasis by Wnt inhibitor. First, we found that KRAS(G12V) induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRAS(G12V) cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRAS(G12D) induced higher activation of RhoA and suppressed activation of Wnt/beta-catenin in H838KRAS(G12D) cells. The restored activation of Wnt/beta-catenin in H838KRAS(G12D) cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRAS(G12V)-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRAS(G12V) driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRAS(G12V)/KRAS(G12D) is distinct.