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Hepatocellular carcinoma ( HCC ) is the most common type of primary liver cancer and the third leading cause of cancer‐related deaths worldwide. Limitations in  HCC  treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only  FDA  approved drug available for advanced  HCC  patients, and development of second‐line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib‐resistant cells from Huh7 and Mahlavu cell lines by long‐term sorafenib exposure. Sorafenib‐resistant  HCC  cells acquired spindle‐shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long‐term sorafenib treatment,  HCC  cells showed induction of hepatocyte growth factor ( HGF ) synthesis and secretion along with increased levels of c‐Met kinase and its active phosphorylated form, indicating autocrine activation of  HGF /c‐Met signaling. Importantly, the combined treatment of the resistant cells with c‐Met kinase inhibitor  SU 11274 and  HGF  neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib‐induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of  HGF  synthesis leading to autocrine activation of  HGF /c‐Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with  HGF  and c‐Met inhibitors comprise promising candidates for overcoming sorafenib resistance.

cancer science

Elevated hepatocyte growth factor expression as an autocrine c‐Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells