Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint

Abstract

Sorafenib is a multikinase inhibitor approved as the first line treatment for late stage hepatocellular carcinoma (HCC). Due to its significant variation in clinical benefits among patients, defining prognostic biomarkers for sorafenib sensitivity in HCC would allow targeted treatment. Phosphorylated extracellular signaling-regulated kinase (pERK) was proposed to predict the response to sorafenib in HCC, but clinical supports are mixed or even contradictory. Here we found that pERK expression levels are variable in different nodules from individual patient liver. Xenografts derived from resected tumors are resistant to sorafenib inhibition when expressing low levels of pERK. This correlation of low pERK levels and sorafenib resistance is corroborated by histological characterization of chemical-induced and genetic mouse models for pERK-positive and pERK-negative HCC respectively, as well as computed tomography (CT) imaging of patient tumors with validated pERK expression. Mouse and human HCC samples expressing low pERK show strong inflammatory infiltrating cells and significant enrichment of intratumoral CD8+ cytotoxic T lymphocytes that express programmed death receptor-1 (PD-1). These pERK−PD-1+ patients have poorer overall and disease-free survival than pERK+PD-1− patients. In conclusion, our data suggest that anti-PD-1 immunotherapy might complement sorafenib in treating HCC patients by targeting sorafenib-resistant cancer cells, and the dual pERK and PD-1 biomarkers would help HCC patient selection to achieve optimal clinical benefits.

Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma

“…This is consistent with the recent findings of the Zhang et al. in vitro study and our previous study .To explore the underlying mechanisms, we carried out RNA‐seq to discover gene expression changes with Sorafenib treatment in HCC cell lines that differentially express pERK (HepG2 and HCC‐0010). We found out that there were significantly more genes whose expression levels changed over fourfold after Sorafenib treatment in the HepG2 cells relative to HCC‐0010 cells (Table ).…”

“…To examine the efficacy of Sorafenib on individual tumors, we generated patient‐derived xenografts using surgically removed HCC tissue. Unfortunately, we could only recruit three pairs of patient‐derived primary HCC xenografts at that time, and our results may have suffered from selection bias .…”

“…Our investigations revealed that the growth rates of tumors with high levels of pERK expression in patient‐derived xenografts were significantly decreased by Sorafenib treatment, while the tumor with low or no expression of pERK did not react to Sorafenib. We previously reported results from 3 pairs of patient‐derived xeonografts . Here, we recruited another 5 pairs of xenografts, originated from 10 different patients for further in vivo validation.…”

A microRNA‐7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib‐resistant cells in human hepatocellular carcinoma

“…In HCC, SR may be inherent wherein the cancer cells typically express less phospho‐ERK and phosphatase and tensin homolog but more phospho‐AKT . More commonly, however, resistance is acquired where the cells augment critical cell‐autonomous survival mechanisms by, for example, increasing expression of EGFR or exploiting noncancerous cells of the tumor microenvironment, to sustain a drug‐resistant tumor‐permissive niche.…”

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges

“…By inducing sorafenib‐resistant HCC cell lines, they found that highly upregulated DNMT1 was positively correlated with PD‐L1 overexpression in sorafenib‐resistant HCC cells. Chen et al revealed that pERK‐negative, PD‐1‐positive patients have poorer OS and DFS than pERK‐positive, PD‐1‐negative patients. Accordingly, patients with pERK‐positive, PD‐1‐positive HCC, a minor population (less than 10%) but the one with the worst postoperative recurrence, might benefit the most from combination therapy with anti‐PD‐1 antibody and sorafenib.…”