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

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

doi:10.1371/journal.pone.0064260

Abstract

BackgroundThe 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 & ResultsPaired 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.ConclusionsmRNA expression analysis of actionable molecules could provide the rationale for new companion diagnostics-based therapeutic strategies in the treatment of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy
Conclusions: mRNA expression analysis of actionable molecules could provide the rationale for new companion diagnostics-based therapeutic strategies in the treatment of hepatocellular carcinoma (HCC)
EGFR mRNA expression was increased in tumors diagnosed at BCLC stage A (1.64 fold, P = 0.002) and this expression pattern was maintained in BCLC stage B tumors (Fig. 1A)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. HCC is the sixth most common cancer and the third most common cause of cancer mortality in the world [1]. Many molecular targeted drugs have entered clinical trials as palliative and adjuvant treatments for HCC [2]. The multikinase inhibitor sorafenib was approved for the first-line therapy in advanced HCC as a result of a statistically significant but modest improvement of overall survival and time to progression in two randomized controlled trials [3,4]. Other molecular targeted drugs have been tested in combination with sorafenib or in the adjuvant setting [5,6]. The limited benefits of current molecular targeted agents including sorafenib have raised an urgent need for new therapeutic strategies in HCC [7]. The effectiveness of molecular targeted agents is modest in hepatocellular carcinoma (HCC).

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