Research Papers:

pERK/pAkt phenotyping in circulating tumor cells as a biomarker for sorafenib efficacy in patients with advanced hepatocellular carcinoma

Jun Li, Lehua Shi, Xiaofeng Zhang, Bin Sun, Yefa Yang, Naijian Ge, Huiying Liu, Xia Yang, Lei Chen, Haihua Qian, Mengchao Wu and Zhengfeng Yin _

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Oncotarget. 2016; 7:2646-2659. https://doi.org/10.18632/oncotarget.6104

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Jun Li1,*, Lehua Shi1,*, Xiaofeng Zhang1,*, Bin Sun1, Yefa Yang1, Naijian Ge1, Huiying Liu1, Xia Yang1, Lei Chen1, Haihua Qian1, Mengchao Wu1, Zhengfeng Yin1

1Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Zhengfeng Yin, e-mail: yinzfk@aliyun.com

Keywords: ERK/Akt, circulating tumor cells, hepatocellular carcinoma, sorafenib

Received: June 16, 2015     Accepted: October 13, 2015     Published: October 26, 2015


Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, therapeutic response to sorafenib was not equal among HCC patients. Here we present a novel system to provide quantitative information concerning sorafenib-related targets by simultaneous detection of phosphorylated ERK (pERK) and pAkt expressions in circulating tumor cells (CTCs) isolated from HCC patients. Our results showed that 90.0% of patients had a molecular classification of tissues concordant with that of CTCs. CTC counts showed a shaper decline in patients with pERK+/pAkt CTCs after two weeks of sorafenib treatment (P < 0.01). Disease control rates were significantly different between patients with pERK+/pAkt CTCs (11/15; 73.3%) and those without (13/44; 29.5%) (P < 0.05). Univariate and multivariate analysis indicated pERK+/pAkt− CTCs as an independent predictive factor of progression-free survival (PFS) (hazard ratio = 9.389; P < 0.01). PFS correlated with the proportion of pERK+/pAkt CTCs (r = 0.968, P < 0.01), and was higher in patients with ≥ 40% pERK+/pAkt− CTCs compared to those with < 40% (8.4 vs. 1.3 mo; P < 0.05). In a validation set of twenty HCC patients, CTCs from patients with ≥ 40% pERK+/pAkt CTCs had significantly higher inhibition rates of spheroid formation compared to those with < 40% (61.2 vs. 19.8%; P < 0.01). Our findings demonstrated that CTCs can be used in place of tumor tissue for characterization of pERK/pAkt expression. pERK+/pAkt CTCs are most sensitive to sorafenib and an independent predictive factor of PFS in HCC patients treated with sorafenib.

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