Abstract
Reliable biomarkers are required to predict the response to sorafenib. We investigated genomic variations associated with responsiveness to sorafenib for patients with unresectable hepatocellular carcinoma (HCC). Blood samples from 2 extreme, 2 strong and 3 poor responders to sorafenib were subjected to whole-genome analysis. Then, we validated candidate genomic variations with another 174 HCC patients, and performed in vitro functional analysis and in silico analyses. Genomic data of >96 gigabases/sample was generated at average of ~34X sequencing depth. In total, 1813 genomic variations were matched to sorafenib responses in clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes. From them, 36 variants were within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2). Validation genotyping confirmed sequencing results and revealed patients genotype for rs2257212 in SLC15A2 showed longer progression-free survival (HR = 2.18). In vitro study displayed different response to sorafenib depending on the genotype of SLC15A2. Structural prediction analysis revealed changes of the phosphorylation levels in protein, potentially affecting sorafenib-associated enzymatic activity. Our finding using extreme responder seems to generate robust biomarker to predict the response of sorafenib treatment for HCC.
Highlights
[1] Because this disease is mostly diagnosed at an advance stage, potentially curative therapies are effective in less than 30–40% of Hepatocellular carcinoma (HCC) patients. [2, 3] While systemic therapies are indicated for advanced HCC, no effective systemic therapy for patients www.impactjournals.com/oncotarget with advanced HCC existed until the development of sorafenib therapy
Two phase III clinical trials have shown that about 50–60 percent of the study subjects are non-responders to sorafenib treatment, and reliable biomarkers are needed for predicting treatment responses prior to therapy initiation. [8, 9] In practice, identification of good responders to sorafenib treatment may be critical for personalized therapy for management of advanced HCC
[14] Previous biomarker response studies have evaluated the correlation between plasma angiogenesis biomarkers, alpha-fetoprotein (AFP) level or vascular permeability-perfusion of dynamic magnetic resonance imaging, and responses to sorafenib in patients with advanced HCC. [15,16,17] finding reliable biomarkers is not an easy task and none of biomarkers are clinically applicable to date
Summary
Hepatocellular carcinoma (HCC) is one of the most common types of cancers (with the highest prevalence in the Asia-Pacific region) and the third leading cause of cancer death worldwide. [1] Because this disease is mostly diagnosed at an advance stage, potentially curative therapies are effective in less than 30–40% of HCC patients. [2, 3] While systemic therapies are indicated for advanced HCC, no effective systemic therapy for patients www.impactjournals.com/oncotarget with advanced HCC existed until the development of sorafenib therapy. Sorafenib is known to inhibit receptor tyrosine kinases in cell membranes (e.g., vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/ threonine kinases (e.g., Raf-1, wild-type B-Raf, and mutant B-Raf). These kinases are involved in tumor cell proliferation and tumor angiogenesis. [8, 9] In practice, identification of good responders to sorafenib treatment may be critical for personalized therapy for management of advanced HCC No such reliable biomarkers or clinical factors currently have been identified to date. Understanding the reasons for such differential responses is essential as is identifying stratification factors such as tumor molecular profiles and individual genetic differences in drug metabolism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
