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

Abstract

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 SU11274 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.

Inhibition of Cyclin‐Dependent Kinase 5

“…Compensatory activation of growth factor signaling including EGF‐, insulin‐like growth factor‐, fibroblast growth factor‐, or hepatocyte growth factor signaling was described as a mechanism of HCC to adapt to sorafenib treatment . In line, our results corroborated compensatory activation of growth factor receptor signaling by sorafenib.…”

c-MET as a Potential Therapeutic Target in Ovarian Clear Cell Carcinoma

“…Firtina Karagonlar et al . reported that SU11274 reversed the increased migration and invasion ability of sorafenib-resistant hepatocellular carcinoma cells37. In ovarian cancer, in vitro study, demonstrated that SU11274 reduced cell growth, motility, and invasive activity of EOC cells16.…”

Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study

“…MET pathway activation and dysregulation have been implicated in multiple cancers, including hepatocellular carcinoma (HCC) [1, 2], and may play a role in resistance to antiangiogenic therapy [3–6]. Similarly, increased expression of the receptor tyrosine kinase AXL has also been reported in HCC and may promote invasive behavior [7].…”