The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

Abstract

A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

“…Sorafenib resistance prompts the need for new therapies to overcome resistance [ 29 ]. Multiple mechanisms underlying impaired sensitivity to sorafenib in HCC have been investigated, including Wnt/β-catenin, TGFβ, Ras/MEK/ERK, PI3K/Akt, TNFα/NF-κB, and JAK/STAT pathways, autophagy, epithelial-mesenchymal transition, cancer stem cells, tumor microenvironment, and epigenetic regulation (involving miR-222, miR-494, miR-21 and miR122) [ 3 ]. To overcome sorafenib resistance and lower its onset concentration, efforts were made to develop combined therapies [ 30 – 34 ].…”

“…However, drug resistance limits its efficacy. Although some mechanisms have been reported for sorafenib resistance, such as epithelial-mesenchymal transition, the proliferation of cancer stem cells, and metabolic reprogramming, the exact cause is still elusive [ 3 ]. Therefore, understanding the underlying molecular basis of HCC sorafenib resistance and developing mechanism-based therapies are urgently needed.…”

MTDH Inhibits K48-Linked Degradation of TAK1 and Promotes Sorafenib Resistance in Hepatocellular Carcinoma

“…[3] As we previous reviewed, the underlying mechanisms of sorafenib resistance involves various cellular processes, complex regulatory signaling network, genetic and epigenetic regulations, and tumor microenvironment. [4] Based on these researches, numerous drugs including small molecule agonists or inhibitors, epigenetic, metabolic, or microenvironmental modulators, stemness inhibitors, oxidative stress inducers, and even nucleic acid therapies were being explored in combination with sorafenib to improve HCC patients outcomes. [4][5][6] However, none of them had been applied in clinical use.…”

“…[4] Based on these researches, numerous drugs including small molecule agonists or inhibitors, epigenetic, metabolic, or microenvironmental modulators, stemness inhibitors, oxidative stress inducers, and even nucleic acid therapies were being explored in combination with sorafenib to improve HCC patients outcomes. [4][5][6] However, none of them had been applied in clinical use. Hence, identifying targets especially those with multiple signals convergence or divergence, to overcome sorafenib resistance is of great clinical signi cance.…”

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

“…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.…”