Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

Abstract

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.

Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

“…In addition, an imbalance between anti-apoptotic and pro-apoptotic proteins is associated with sorafenib resistance. Nonetheless, the exact underlying mechanism of sorafenib resistance needs to be further elucidated (112).…”

Novel insights into the progression and prognosis of the calpain family members in hepatocellular carcinoma: a comprehensive integrated analysis

“…Recently, a study showed that tremelimumab plus durvalumab (STRIDE) had a median OS of 16.43 months compared to sorafenib with a median OS of 13.77 months in unresectable HCC ( Kudo, 2022 ). However, HCC is a highly heterogeneous cancer with substantial genomic heterogeneity, which influences the cellular response of systemic therapy such as sorafenib and ICIs ( Atwa et al, 2021 ). For patients with resistance to sorafenib (first-line therapy) in advanced HCC, regorafenib (RESORCE), cabozantinib (CELESTIAL), ramucirumab (REACH-2), nivolumab in combination with ipilimumab (CheckMate 040), or pembrolizumab (Keynote 240) were recommended ( Solimando et al, 2022 ).…”

Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle

“…The mechanism of HCC primary resistance to ICIs seems to encompass both tumor intrinsic and micro-environment (TME) levels [14]. Among the former, WNT/CTNNTB1 somatic mutation has the soundest evidence to promote HCC immune escape [15], along with the expression of multiple immune checkpoints such as lymphocyte-activation gene 3 (LAG-3), fibrinogen-like protein1(FGL1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT)-nectin cell adhesion molecule 2 (NECTIN2) and CD 155. Different immune cell populations and epigenetic mechanisms are top players in TME-related resistance to ICIs.…”