Hepatocellular carcinoma resistance to tyrosine kinase inhibitors: Current status and perspectives

Abstract

The study conducted by Wang et al, focuses on the role of Rho GTPase activating protein 12 (ARHGAP12), in hepatocellular carcinoma (HCC). This research reveals that ARHGAP12 expression, markedly elevated in malignant cells of HCC, correlates strongly with adverse outcomes for patients. Furthermore, the study illustrates that ARHGAP12 enhances the ability of HCC cells to invade and contributes to their resistance to tyrosine kinase inhibitors (TKIs) through modulation of the focal adhesion pathway. To comprehensively investigate the relationship between ARHGAP12 and TKI resistance, this study integrates single-cell and bulk RNA sequencing methodologies along with data from tumor immune single-cell hub 2, Gene Expression Omnibus, The Cancer Genome Atlas, CellMiner, Genomics of Drug Sensitivity in Cancer 2, as well as immunohistochemical staining and proteomic analyses. Statistical analyses, including the Wilcoxon rank-sum test and receiver operating characteristic curve analysis, were employed to evaluate the correlation between ARHGAP12 expression levels and clinical parameters, as well as drug sensitivity. It is evident that a more profound exploration of the molecular dynamics of HCC, especially those related to resistance against TKIs, is essential.

Keywords: Tyrosine kinase inhibitor; Hepatocellular carcinoma; Resistance; Cancer therapy; Rho GTPase activating protein 12

Core Tip: This study reveals the potential clinical value of Rho GTPase activating protein 12 (ARHGAP12) and provided the target direction for clinical tyrosine kinase inhibitor resistance and highlights the potential role of ARHGAP12 in drug resistance by revealing its involvement in the focal adhesion pathway. Through gene enrichment and protein-protein interaction network analyses, it was found that ARHGAP12 might regulate integrin beta 1, impacting cell attachment, migration, and cytoskeleton interactions.