Gene Signature for Sorafenib Susceptibility in Hepatocellular Carcinoma: Different Approach with a Predictive Biomarker

Chang Min Kim, Shin Hwang, Bhumsuk Keam, Yun Suk Yu, Ji Hoon Kim, Dong Sik Kim, Si Hyun Bae, Gun Do Kim, Jong Kyu Lee, Yong Bae Seo, Soon Woo Nam, Koo Jeong Kang, Luigi Buonaguro, Jin Young Park, Yun Soo Kim, Hee Jung Wang

Research output: Contribution to journalArticle

Abstract

Background/Aim: Uniform treatment of hepatocellular carcinoma (HCC) with molecular targeted drugs (e.g., sorafenib) results in a poor overall tumor response when tumor subtyping is absent. Patient stratification based on actionable gene expression is a method that can potentially improve the effectiveness of these drugs. Here we aimed to identify the clinical application of actionable genes in predicting response to sorafenib. Methods: Through quantitative real-time reverse transcription PCR, we analyzed the expression levels of seven actionable genes (VEGFR2, PDGFRB, c-KIT, c-RAF, EGFR, mTOR, and FGFR1) in tumors versus noncancerous tissues from 220 HCC patients treated with sorafenib. Our analysis found that 9 responders did not have unique clinical features compared to nonresponders. A receiver operating characteristic curve evaluated the predictive performance of the treatment benefit score (TBS) calculated from the actionable genes. Results: The responders had significantly higher TBS values than the nonresponders. With an area under the curve of 0.779, a TBS combining mTOR with VEGFR2, c-KIT, and c-RAF was the most significant predictor of response to sorafenib. When used alone, sorafenib had a 0.7-3% response rate among HCC patients, but when stratifying the patients with actionable genes, the tumor response rate rose to 15.6%. Furthermore, actionable gene expression is significantly correlated with tumor response. Conclusions: Our findings on patient stratification based on actionable molecular subtyping potentially provide a therapeutic strategy for improving sorafenib's effectiveness in treating HCC.

Original languageEnglish
Pages (from-to)182-192
Number of pages11
JournalLiver Cancer
Volume9
Issue number2
DOIs
Publication statusPublished - Apr 1 2020

Keywords

  • Biomarker
  • Gene signature
  • Hepatocellular carcinoma
  • Sorafenib

ASJC Scopus subject areas

  • Hepatology
  • Oncology

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    Kim, C. M., Hwang, S., Keam, B., Yu, Y. S., Kim, J. H., Kim, D. S., Bae, S. H., Kim, G. D., Lee, J. K., Seo, Y. B., Nam, S. W., Kang, K. J., Buonaguro, L., Park, J. Y., Kim, Y. S., & Wang, H. J. (2020). Gene Signature for Sorafenib Susceptibility in Hepatocellular Carcinoma: Different Approach with a Predictive Biomarker. Liver Cancer, 9(2), 182-192. https://doi.org/10.1159/000504548