The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma

Abstract

Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.

Keywords: drug resistance; hepatocellular carcinoma; immune checkpoint inhibitor; lenvatinib; molecular target agent; regorafenib; sorafenib; systemic therapy; tumor microenvironment; tyrosine kinase.

Figure 1

Schematic representation of epigenetic modifications in hepatocellular carcinoma (HCC). Histone proteins undergo various post-translational modifications by enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases (HMTs) to alter chromatin structure and modulate gene expression by providing transcriptional activators or repressors access to DNA sequences. Methylation of CpG sites, which are upstream regulatory elements of DNA found in promoters, enhancers, and transcription factor-binding sites, are mediated by enzymes such as DNA (cytosine-5)-methyltransferase 1 (DNMT1), DNMT3A, and DNMT3B, which suppress the activity and expression of tumor suppressor genes. Among non-coding RNA (ncRNA) that do not encode proteins or peptides, long ncRNAs (lncRNAs) and microRNAs (miRNAs) regulate gene expression at various levels, including transcription, translation, and protein function. These epigenetic modifications are also associated with various processes involved in tumor growth, metastasis, and drug resistance of HCC. Red arrows indicate increased expression and blue arrows indicate decreased expression. MOF, males absent on the first; FBP, fructose-1,6-bisphosphatase; VEGF, vascular endothelial growth factor; EZH2, enhancer zeste homolog 2; C/EBPβ, CCAAT/enhancer-binding protein-beta; PGK1, phosphoglycerate kinase 1; PDHK1, pyruvate dehydrogenase kinase 1; APC, adenomatosis polyposis coli; CDKN2A, cyclin-dependent kinase inhibitor 2A; NANR, HCC-associated lncRNA; ARSR, NR2F1-AS1, nuclear receptor subfamily 2 group F member 1-antisense RNA 1; HULC, highly upregulated in liver cancer; MALAT1, metastasis-associated lung adenocarcinoma transcript 1.