Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Sorafenib is the first multi-tyrosine kinase inhibitor approved for HCC and it has represented the standard of care for advanced HCC for almost 10 years, offering a survival benefit when compared to placebo. However, this benefit is limited, showing rare objective responses and a disease control rate approaching 50–60%, with most patients experiencing disease progression at 6 months. These scant results dictate the urgent need for strategies to overcome both primary and acquired resistance. Herein we report several mechanisms supporting resistance to sorafenib in HCC patients, including activation of oncogenic pathways. Among these, the AKT/mTOR pathway plays a crucial role being at the crossroad of multiple driving events. Autophagy, multidrug-resistant phenotype, hypoxia-related mechanisms and endoplasmic reticulum stress are gaining more and more relevance as crucial events driving the response to anticancer drugs, including sorafenib. Several HCC-specific miRNAs take part to the regulation of these cellular processes. Remarkably, molecularly targeted strategies able to overcome resistance in these settings have also been reported. So far, the vast majority of data has been derived from laboratory studies, which means the need for an extensive validation. Indeed, most of the possible drug associations displaying promising effects in improving sorafenib efficacy herein described derive from preclinical explorations. Notably, data obtained in animal models can be inconsistent with regard to the human disease for efficacy, safety, side effects, best formulation and pharmacokinetics. However, they represent the necessary preliminary step to improve the management of advanced HCC.

Targeting Akt in cancer for precision therapy

“…Alternatively, inhibition of Akt by some natural agents may be valuable for cancer chemoprevention and therapy [ 285 , 286 ]. Since Akt activation confers resistance to anticancer agents such as the multikinase inhibitor sorafenib, the ER antagonists tamoxifen and fulvestrant [ 219 , 287 – 289 ], combination of Akt inhibitors and other anticancer agents may improve the efficacy of cancer therapy.…”

The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

“…Under hypoxic conditions, the SUMOylation of GLI proteins can be upregulated [ 74 ]. GLI is an essential mediator of the SHh pathway signal transfer [ 88 ]. SHh can promote the drug resistance of liver cancer cells, so it has become an essential target for the development of drug resistance.…”

Roles of lncRNAs Mediating Wnt/β-Catenin Signaling in HCC

“…Liver cancer has become one of most prevalent malignant diseases worldwide, and hepatocellular carcinoma (HCC) accounts for most liver cancer cases (1)(2)(3). Owing to the increasing incidence and mortality, HCC is considered the second most deadly cancer worldwide (4).…”