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

• Published in: International Journal of Molecular Sciences Vol. 24; no. 3; p. 2805
• Main Authors: Oura, Kyoko, Morishita, Asahiro, Hamaya, Sae, Fujita, Koji, Masaki, Tsutomu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2023; MDPI
• Subjects: Cancer therapies; Carcinoma, Hepatocellular; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Chemoembolization, Therapeutic; Cyclin-dependent kinases; DNA methylation; Enzymes; Epigenesis, Genetic; Epigenetics; Gene amplification; Gene expression; Genomes; Hepatitis C; Humans; Immune checkpoint inhibitors; Inhibitor drugs; Kinases; Liver cancer; Liver cirrhosis; Liver Neoplasms; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Mutation; Proteins; Review; Targeted cancer therapy; Transcription factors; Tumor Microenvironment; Tumor Microenvironment - genetics; immune checkpoint inhibitor; lenvatinib; sorafenib; tyrosine kinase; molecular target agent; drug resistance; regorafenib; tumor microenvironment; systemic therapy; hepatocellular carcinoma
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032805

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.