Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma

BACKGROUND AND PURPOSE: As a highly heterogeneous cancer, hepatocellular carcinoma (HCC) shows different response rates to the multi-kinase inhibitor lenvatinib. Thus, it is important to explore genetic biomarkers for precision lenvatinib therapy in HCC. EXPERIMENTAL APPROACH: The effect and mechanism of AXIN1 mutation on HCC were revealed by cell proliferation assay, long-term clone formation assay, sphere formation assay and small molecule inhibitor library screening. A new therapeutic strategy targeting HCC with AXIN1 mutation was evaluated in humanized models (patient-derived xenograft [PDX] and patient-derived organoid [PDO]). KEY RESULTS: Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo. CONCLUSION AND IMPLICATIONS: AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.