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Review
. 2017 May;38(5):614-622.
doi: 10.1038/aps.2017.5. Epub 2017 Mar 27.

New knowledge of the mechanisms of sorafenib resistance in liver cancer

Yan-Jing Zhu  1 , Bo Zheng  1 , Hong-Yang Wang  1   2 , Lei Chen  1   2
Affiliations
Review

New knowledge of the mechanisms of sorafenib resistance in liver cancer

Yan-Jing Zhu et al. Acta Pharmacol Sin. 2017 May.

Abstract

Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique _target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.

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Figures

Figure 1
Figure 1
Cellular _targets of sorafenib. Sorafenib blocks receptor tyrosine kinase signaling (VEGFR, PDGFR, c-Kit and RET) and inhibits downstream Raf serine/threonine kinase activity to prevent tumor growth by anti-angiogenic, antiproliferative and/or pro-apoptotic effects (from Bayer website).
Figure 2
Figure 2
Kaplan-meier analysis of overall survival in the SHARP trial.
Figure 3
Figure 3
Kaplan-meier analysis of overall survival in the Asian-Pacific trial.
Figure 4
Figure 4
Mechanism of sorafenib resistance in liver cancer. Sorafenib's broad-spectrum anti-tumor effect has brought new inspiration; however, side effects and drug resistance have hampered its use clinically. How to improve the clinical efficacy has become an urgent problem. On the one hand, tumor genome sequencing technology is expected to make it possible to predict the effect of sorafenib by defining novel molecular markers. On the other hand, sorafenib combined with other molecular _targeted drugs or traditional treatments may play more important role for individual treatment in future.
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