Actionable Gene Expression-Based Patient Stratification for Molecular Targeted Therapy in Hepatocellular Carcinoma

Jung Hee Kwon, Namgyu Lee, Jin Young Park, Yun Suk Yu, Jin Pyo Kim, Ji Hye Shin, Dong-Sik Kim, Jae Won Joh, Dae Shick Kim, Kwan Yong Choi, Koo Jeong Kang, Gundo Kim, Young Ho Moon, Hee Jung Wang

Research output: Contribution to journalArticle

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Abstract

Background:The effectiveness of molecular targeted agents is modest in hepatocellular carcinoma (HCC). Efficacy of molecular targeted therapies has been better in cancer patients with high expression of actionable molecules defined as cognate target molecules. However, patient stratification based on the actionable molecules dictating the effectiveness of targeted drugs has remained understudied in HCC.Experimental Design & Results:Paired tumor and non-tumoral tissues derived from a total of 130 HCC patients were studied. Real-time RT-PCR was used to analyze the mRNA expression of actionable molecules in the tissues. mRNA levels of EGFR, VEGFR2, PDGFRβ, FGFR1, and mTOR were up-regulated in tumors compared to non-tumors in 35.4, 42.3, 61.5, 24.6, and 50.0% of patients, respectively. Up-regulation of EGFR was observed at early stage and tended to gradually decrease toward late stages (BCLC stage A: 41.9%; B: 30.8%; C: 17.6%). Frequency of VEGFR2 expression in tumors at stage C was lower than that in the other stages (BCLC stage A: 45.9%; B: 41.0%; C: 29.4%). PDGFRβ and mTOR were observed to be up-regulated in more than 50% of tumors in all the stages whereas FGFR1 was up-regulated in only about 20% of HCC irrespective of stages. A cluster analysis of actionable gene expression revealed that HCC can be categorized into different subtypes that predict the effectiveness of molecular targeted agents and combination therapies in clinical trials. Analysis of in vitro sensitivity to sorafenib demonstrated that HCC cells with up-regulation of PDGFRβ and c-Raf mRNA are more susceptible to sorafenib treatment in a dose and time-dependent manner than cells with low expression of the genes.Conclusions:mRNA expression analysis of actionable molecules could provide the rationale for new companion diagnostics-based therapeutic strategies in the treatment of HCC.

Original languageEnglish
Article numbere64260
JournalPLoS One
Volume8
Issue number6
DOIs
Publication statusPublished - 2013 Jun 13

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Molecular Targeted Therapy
hepatoma
Gene expression
Hepatocellular Carcinoma
Tumors
Gene Expression
gene expression
therapeutics
Molecules
Messenger RNA
neoplasms
Neoplasms
Tissue
Up-Regulation
Cluster analysis
Design of experiments
Genes
Therapeutics
Cluster Analysis
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Kwon, J. H., Lee, N., Park, J. Y., Yu, Y. S., Kim, J. P., Shin, J. H., ... Wang, H. J. (2013). Actionable Gene Expression-Based Patient Stratification for Molecular Targeted Therapy in Hepatocellular Carcinoma. PLoS One, 8(6), [e64260]. https://doi.org/10.1371/journal.pone.0064260

Actionable Gene Expression-Based Patient Stratification for Molecular Targeted Therapy in Hepatocellular Carcinoma. / Kwon, Jung Hee; Lee, Namgyu; Park, Jin Young; Yu, Yun Suk; Kim, Jin Pyo; Shin, Ji Hye; Kim, Dong-Sik; Joh, Jae Won; Kim, Dae Shick; Choi, Kwan Yong; Kang, Koo Jeong; Kim, Gundo; Moon, Young Ho; Wang, Hee Jung.

In: PLoS One, Vol. 8, No. 6, e64260, 13.06.2013.

Research output: Contribution to journalArticle

Kwon, JH, Lee, N, Park, JY, Yu, YS, Kim, JP, Shin, JH, Kim, D-S, Joh, JW, Kim, DS, Choi, KY, Kang, KJ, Kim, G, Moon, YH & Wang, HJ 2013, 'Actionable Gene Expression-Based Patient Stratification for Molecular Targeted Therapy in Hepatocellular Carcinoma', PLoS One, vol. 8, no. 6, e64260. https://doi.org/10.1371/journal.pone.0064260
Kwon, Jung Hee ; Lee, Namgyu ; Park, Jin Young ; Yu, Yun Suk ; Kim, Jin Pyo ; Shin, Ji Hye ; Kim, Dong-Sik ; Joh, Jae Won ; Kim, Dae Shick ; Choi, Kwan Yong ; Kang, Koo Jeong ; Kim, Gundo ; Moon, Young Ho ; Wang, Hee Jung. / Actionable Gene Expression-Based Patient Stratification for Molecular Targeted Therapy in Hepatocellular Carcinoma. In: PLoS One. 2013 ; Vol. 8, No. 6.
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abstract = "Background:The effectiveness of molecular targeted agents is modest in hepatocellular carcinoma (HCC). Efficacy of molecular targeted therapies has been better in cancer patients with high expression of actionable molecules defined as cognate target molecules. However, patient stratification based on the actionable molecules dictating the effectiveness of targeted drugs has remained understudied in HCC.Experimental Design & Results:Paired tumor and non-tumoral tissues derived from a total of 130 HCC patients were studied. Real-time RT-PCR was used to analyze the mRNA expression of actionable molecules in the tissues. mRNA levels of EGFR, VEGFR2, PDGFRβ, FGFR1, and mTOR were up-regulated in tumors compared to non-tumors in 35.4, 42.3, 61.5, 24.6, and 50.0{\%} of patients, respectively. Up-regulation of EGFR was observed at early stage and tended to gradually decrease toward late stages (BCLC stage A: 41.9{\%}; B: 30.8{\%}; C: 17.6{\%}). Frequency of VEGFR2 expression in tumors at stage C was lower than that in the other stages (BCLC stage A: 45.9{\%}; B: 41.0{\%}; C: 29.4{\%}). PDGFRβ and mTOR were observed to be up-regulated in more than 50{\%} of tumors in all the stages whereas FGFR1 was up-regulated in only about 20{\%} of HCC irrespective of stages. A cluster analysis of actionable gene expression revealed that HCC can be categorized into different subtypes that predict the effectiveness of molecular targeted agents and combination therapies in clinical trials. Analysis of in vitro sensitivity to sorafenib demonstrated that HCC cells with up-regulation of PDGFRβ and c-Raf mRNA are more susceptible to sorafenib treatment in a dose and time-dependent manner than cells with low expression of the genes.Conclusions:mRNA expression analysis of actionable molecules could provide the rationale for new companion diagnostics-based therapeutic strategies in the treatment of HCC.",
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AU - Kim, Jin Pyo

AU - Shin, Ji Hye

AU - Kim, Dong-Sik

AU - Joh, Jae Won

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