Abstract
Simple SummaryHepatocellular carcinoma (HCC) represents a worldwide health challenge, ranking globally as the third most common cause of cancer-related mortality. Current advancements in the HCC therapeutic armamentarium succeeded in challenging HCC conventional therapy. Systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs) come at the forefront of novel HCC therapeutic modalities. However, emerging drug resistance remains an obstacle during HCC therapy. According to the ongoing genomic analysis of HCC, a complex mutational landscape lies behind HCC pathogenesis and hence, affects the response of the tumor to the applied therapy. This review aims at categorizing and summarizing the different resistance mechanisms confronting tyrosine kinase inhibitors, represented by sorafenib, as well as ICIs, during HCC therapy. In addition, giving an insight into how genomic heterogeneity can influence the response of HCC to the aforementioned therapies.Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.
Highlights
Liver cancer ranks globally as the third leading cause of cancer-related mortality [1]with hepatocellular carcinoma (HCC) accounting for 70–90% of total primary liver cancers [2]
Zheng et al has deduced that the homozygous genotype for the C allele is associated with a shorter overall survival (OS) in HCC patients treated with sorafenib [41]
An ePHAS study has reported that the presence of a specific haplotype of endothelial nitric oxide synthase (eNOS)-786 and eNOS VNTR polymorphisms may identify a subset of HCC patients who are more resistant to sorafenib [43]
Summary
Liver cancer ranks globally as the third leading cause of cancer-related mortality [1]. Molecular targeted therapy has witnessed a major breakthrough with the approval of sorafenib [4,5] Both the SHARP and Asia-Pacific trials engaged in sorafenib approval and revealed a significant improvement in survival benefit of advanced. A decade thereafter, phase II and III clinical trials were inaugurated, to test several molecularly targeted mediators, though most of such trials showed non-superiority in survival benefits for advanced HCC patients or treatments were accompanied with severe adverse effects [6]. Engagement of co-inhibitory receptors with their ligands is one arm of escaping immune surveillance through attenuating the cytotoxic activity of T cells and tumor progression [11] This was one rationale for developing immunotherapeutic techniques for HCC [12], as inhibition of immune checkpoints can aid at leveraging the anti-tumor immune response mediated through cytotoxic T cells. Criteria for inclusion were complete, relevant publication, available online, in English, published mostly between 2008 and 2020
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