Overcoming sorafenib treatment-resistance in hepatocellular carcinoma: A future perspective at a time of rapidly changing treatment paradigms

Hepatocellular carcinoma (HCC) has become the second leading cause of cancer-related death in the world due to a steady increase in the incidence rate, typical liver damage, and limited efficacy offered by the existing therapies for advanced stages of the disease. Systemic therapy with tyrosine kinase inhibitors is now recommended by most guidelines for patients not eligible for locoregional therapies, including those who have undergone surgical resection, liver transplantation or tumor ablation. However, the efficacy of systemic therapy remains limited despite the significant developments made in this area [1].

Sorafenib was consistently shown to be beneficial for patients with advanced HCC in multiple phase III trials conducted since 2007 [2]. Sorafenib is a multi-kinase inhibitor that is considered as an anti-angiogenic drug because of its inhibitory effect on the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathways. However, sorafenib has been shown to elicit numerous off-target effects in other cellular regulatory pathways including RAF1, PDGFRs, KIT as well as on other kinases [3]. Thus, sorafenib treatment is expected to have pleiotropic effects on HCC and other cell types within the tumor microenvironment (TME) including but not limited to infiltrating stellate cells and immune cells [3]. Understanding these complex effects is critical, as the exact mechanisms of benefit remain unclear, treatment responses are rare and transient, and the occurrence of resistance is common – with overall increases in survival of only 3 months.

Since 2017, the treatment options for advanced HCC have expanded beyond sorafenib. Based on successful randomized phase III trials, two other multitargeted tyrosine kinase inhibitors (regorafenib and cabozantinib) are now approved as a second-line treatment for patients with sorafenib-resistant HCC [2]. Similarly, an anti-VEGFR2 antibody (ramucirumab) was approved in this setting for patients with high levels (>400 ng/ml) of alphafetoprotein [2]. These approaches have demonstrated an increased median overall survival between 1 and 3 months but, as with sorafenib, they failed to show durable therapeutic responses. Preliminary data from the use of immune checkpoint blockers (ICBs) has shown some encouraging durable responses in approximately 15% of the patients, even in those who received prior sorafenib treatment [2]. However, two recently completed randomized phase III trials of ICBs have failed to reach the prespecified trial endpoints of increased progression-free and overall survival in patients who progressed while undergoing treatment with sorafenib. Thus, defining the underlying mechanisms of sorafenib resistance is still of great significance.

In this issue of EBioMedicine, Xia et al. provide an overview of how the TME and tumor metabolism may mediate sorafenib resistance [4]. Of particular significance, they discuss how the HCC microenvironment and metabolism might regulate cell stemness, mesenchymal state, and resistance to sorafenib via epigenetic mechanisms. The review provides a comprehensive and integrative perspective on the intricate mechanisms of acquired resistance reported for sorafenib using an epithelial-mesenchymal transition and cancer stem cell-based models. Since sorafenib is a multi-target agent that is widely used worldwide, understanding its resistance-associated mechanisms will have great significance not only for establishing clinical biomarkers of response, but may also serve to guide the development of new therapeutic targets. The review appropriately discusses the available evidence regarding sorafenib resistance-associated mechanisms and highlights new avenues in identification of suitable targets that may provide a synergistic effect with sorafenib.

As discussed in the review, an important research question is the role of the specific TME of HCC. The vast majority of HCCs occur with underlying hepatic damage (characterized by pathological liver vascular, inflammatory and pro-fibrotic responses); and highly abnormal TME, also characterized by abnormal angiogenesis, immunosuppression, and fibrosis [5]. It is currently unclear whether sorafenib can overcome these abnormalities in the damaged liver and the TME of HCC. In our research, we found pronounced anti-vascular effects and increased hypoxia, inflammatory/myeloid cell infiltration and fibrosis in the TME of HCC—mediated by stromal-derived factor (SDF)-1α/CXCR4 pathway—after sorafenib treatment in murine models [6]. Preventing these treatment-induced effects using a CXCR4 inhibitor was effective in enhancing sorafenib treatment response and in reprogramming of the TME to enhance responses to sorafenib when combined with ICB [6,7]. It has been reported that sorafenib-induced hypoxia promotes the activation of hypoxia-inducible factor (HIF)-1α and HCC cell resistance to sorafenib [8]. Moreover, analysis of clinical and pathology data showed that tumor-associated neutrophils recruit macrophages and T-regulatory cells in promoting resistance to sorafenib [9]. Besides, tumor metabolism has been implicated in sorafenib resistance, as key enzymes in glycolysis were found to be overexpressed in patients with sorafenib resistant HCC [10]. Overall, these results suggest that inhibiting glycolysis by targeting these key enzymes may be an effective strategy to target treatment resistance, especially under sorafenib-induced hypoxic conditions. They also raise other unanswered questions to elucidate the role of the TME as a target for therapy, in a time of rapidly changing treatment paradigms.

Lenvatinib has shown equivalent efficacy with sorafenib and is increasingly being used as the first-line treatment option [1]. Moreover, a combination of an anti-VEGF antibody with ICB has shown superiority to sorafenib in a phase III trial (IMbrave150 study). These developments have impacted sorafenib's use and the trend is likely to continue. The mechanisms of resistance to sorafenib in such a setting (post-lenvatinib or ICB treatment) are unknown, but future strategies might involve vascular normalization rather than treatments that increase tumor hypoxia [7]. The exact role of sorafenib and tumor metabolism in these rapidly evolving treatment strategies remains to be established.