REVIEWING ADVANCES IN UNDERSTANDING AND TARGETING THE MAPK SIGNALING PATHWAY IN HEPATOCELLULAR CARCINOMA PROGRESSION AND THERAPEUTICS

Abstract

Hepatocellular carcinoma (HCC) is a severe and increasingly prevalent health issue affecting individuals globally. Recent research endeavors in the clinical domains have lately focused more on the MAPK signaling pathway in HCC. Activating mutations in the RAS and RAF genes, which greatly activate the MAPK pathway in malignancies, are rare in HCC patients, yet over 50% of them have activated the pathway. This suggests that other factors may be responsible for the activation of the signaling pathway in HCC. MAPK signaling is important to carcinogenesis, and it is often altered in human cancers. The drug resistance in targeted therapy against RTKs in HCC may arise from mutations in downstream components (RAS, RAF, MEK, ERK), resistant mutations within RTKs, and additional alternative pathways like PI3K and YAP may also develop the resistance. Epigenetic processes and chromatin remodeling are crucial to pharmacological tolerance to MAPK regulation. This review will focus on the latest developments in our knowledge of the cellular and molecular processes to activate the MAPK signaling pathway, as well as possible treatment approaches that specifically target this pathway in relation to HCC. The study also investigates the clinical efficacy of molecular-targeted treatments, including tyrosine kinase inhibitors and immunological checkpoint inhibitors and highlights the use of combination therapy for HCC.