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New Knowledge of the Mechanisms of Sorafenib Resistance in Liver Cancer

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New Knowledge of the Mechanisms of Sorafenib Resistance in Liver Cancer Acta Pharmacologica Sinica (2017) 38: 614–622 © 2017 CPS and SIMM All rights reserved 1671-4083/17 www.nature.com/aps Review New knowledge of the mechanisms of sorafenib resistance in liver cancer Yan-jing ZHU1, #, Bo ZHENG1, #, Hong-yang WANG1, 2, *, Lei CHEN1, 2, * 1International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; 2National Center for Liver Cancer, Shanghai 201805, China 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. Keywords: sorafenib; hepatocellular carcinoma; targeted therapy; drug resistance; individualized treatment Acta Pharmacologica Sinica (2017) 38: 614–622; doi: 10.1038/aps.2017.5; published online 27 Mar 2017 Introduction way. Additionally, sorafenib can inhibit angiogenesis through Since the molecular revolution of the 1980s, knowledge of targeting of the hepatocyte factor receptor (c-Kit), Fms-like the etiology of cancer has increased dramatically, leading to tyrosine kinase (FLT-3), vascular endothelial growth factor the discovery and development of targeted therapies tailored receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor to inhibit cancer-specific pathways. Among the numerous receptor (PDGFR-β) and other tyrosine kinases[6, 7] (Figure 1). molecular targeted drugs, sorafenib, an oral multi-target Preclinical studies have also found that sorafenib is effective kinase inhibitor that is also known as Nexavar, was developed in various tumor cells, such as breast cancer MDA-MB-231 by the Bayer and Onyx companies. Due to its effect on renal (containing G463V b-raf and k-ras gene mutations), melanoma cell carcinoma and hepatocellular carcinoma, sorafenib has LOX, and pancreatic BxPC3 cells, as well as colon cancer been clinically approved for the treatment of advanced renal HCT116, DLD-1 and Colo-205 cells[8, 9] and other tumor cell cell carcinoma and hepatocellular carcinoma (HCC)[1]. More- lines. over, several clinical trials, including those for NSCLC[2], meta- Although sorafenib has opened a window of hope after static thyroid cancer[3], steroid-refractory prostate cancer[4], decades of searching for effective agents to treat HCC, the and metastatic breast cancer[5], with sorafenib as the potential overall outcomes are far from satisfactory. Its side effects have therapeutic strategy are now ongoing. hampered its use; adverse events that have been reported[10] Being a multi-target kinase inhibitor, sorafenib can block in patients receiving sorafenib are predominantly gastroin- tumor cell proliferation by inhibiting the activity of Raf-1, testinal, constitutional, or dermatologic in nature, including B-Raf and kinases in the Ras/Raf/MEK/ERK signaling path- diarrhea, weight loss, and hand–foot skin reactions. In severe cases, it can lead to hypertension, abdominal pain and even discontinuation of therapy. In addition, due to the genetic # These authors contributed equally to this work. heterogeneity of HCC, some patients are initially resistant *To whom correspondence should be addressed. E-mail [email protected] (Lei CHEN); to sorafenib, which has led to the identification of predictive [email protected] (Hong-yang WANG) biomarkers for primary resistance to sorafenib. It has recently Received 2016-11-21 Accepted 2017-01-19 been reported that basal pERK levels, JNK and VEGFA may www.chinaphar.com Zhu YJ et al 615 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[10] (from Bayer website). be candidate predictors of sorafenib response in HCC. The treatment were randomly divided into two groups: one with acquired resistance to sorafenib has also drawn attention. sorafenib treatment of doses of 400 mg, bid and the other as Several mechanisms are involved in the acquired resistance placebo. The results showed that sorafenib was significantly to sorafenib, such as crosstalk involving the PI3K/Akt and associated with a higher median OS (10.7 versus 7.9 months; JAK-STAT pathways, the activation of hypoxia-inducible P=0.0006) and a higher median TTP (5.5 versus 2.8 months; pathways and epithelial-mesenchymal transition, as well as P=0.000007) compared with the placebo group. This showed others. Here, we attempt to describe the function of sorafenib, that sorafenib as a first-line drug for advanced HCC could pro- its clinical application, and molecular mechanisms for drug long the median OS and radiological progression by 3 months resistance, especially for HCC patients. compared with the placebo[13] (Figure 2). Interestingly, Cheng et al[13] reported that the Asian-Pacific portion of the phase III Clinical application in HCC Monotherapy Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver; its annual diagnosis rate ranks fifth in cancers around the globe, and it is also the third major leading cause of cancer-related death[11]. With nearly 700 000 new cases every year, China accounts for over 50% of newly diagnosed HCC worldwide[12]. Because the number of HBV carriers (>120 000 000) in China is large, chronic hepatitis- induced cirrhosis and hepatocyte malignant transformation is the major pathogenic factor for HCC. Due to the lack of effec- tive targeted drugs, there are no standard adjunct therapies following surgical resection at present. According to previ- ous clinical trials, sorafenib displays significant efficacy in the treatment of advanced HCC patients. In 2008, the SHARP (Sorafenib HCC Assessment Random- ized Protocol) trial, a randomized controlled phase III trial for the treatment of HCC in international multi-centers was published in the New England Journal of Medicine[1]. In total, 602 advanced HCC patients who had not received systematic Figure 2. Kaplan-meier analysis of overall survival in the SHARP trial[1]. Acta Pharmacologica Sinica www.nature.com/aps 616 Zhu YJ et al double-blind, randomized, controlled clinical trial of sorafenib DNA and inhibit the synthesis of nucleic acids, and it has treatment also demonstrated that sorafenib could prolong broad-spectrum activity against tumors. Abou-Alfa et al phase the OS of advanced HCC patients by 2.3 months, consistent II clinical trial[18] suggested that the combination of sorafenib with the SHARP trial (Figure 3). Based on this result, the FDA with doxorubicin could synergistically inhibit the prolifera- approved sorafenib for the treatment of unresectable HCC. tion of tumor cells and the formation of new blood vessels in tumor nodules through the “hyperchromic effect.” Further- more, it is necessary to properly optimize the dose intensity of doxorubicin because the AUC (the area under the curve) and Cmax (maximum concentration) of doxorubicin in the human body are limited[19]. Fluorouracil has the ability to inhibit metabolites. It is transformed into 5F-dUMP in tumor cells and can inhibit thymidylate synthase (TS), disturb the synthesis of DNA, and attenuate the proliferation of tumor cells. Petrini et al initi- ated a study to evaluate the clinical potential of a combination drug of sorafenib and low-dose fluorouracil in the treatment of 38 HCC patients, which showed that the mPF and OS were 9.6 and 12.2 months, respectively[20]. The drug had a positive response and could effectively lower the dose intensity of fluo- Figure 3. Kaplan-meier analysis of overall survival in the Asian-Pacific rouracil and therefore reduce adverse effects. [13] trial . Additionally, studies of the combination of sorafenib and uracil-tegafur[21] or octreotide[22] reported a better curative effect when they are used as a combination therapy than when they are used as a monotherapy, which could reduce the dos- Combination with other drugs age of sorafenib and the rate of side effects. Although single-agent sorafenib has an effect on HCC, its adverse effects, such as rash, diarrhea, high blood pressure, Combination with traditional treatment and hand-foot syndrome, limit high-dosage use of sorafenib[14]. According to recent studies, combining sorafenib with tradi- Therefore, it is necessary to combine sorafenib with other tional treatment also has potential clinical utility. Sorafenib drugs to lower its onset concentration. Additionally, although can inhibit the synthesis of VEGF and the formation of new sorafenib is a
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