Oncology Surgery, Cell Therapy and Transplant Organs, Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/IBiS/Universidad de Sevilla, Sevilla, Spain.
Curr Cancer Drug Targets. 2013 Mar;13(3):300-12. doi: 10.2174/15680096113139990075.
The recent discoveries of genomic and molecular markers in hepatocellular carcinoma (HCC) have improved the understanding about the complexity of the signal transduction pathways as well as their relevance in normal and liver cancer cells. The identification of the functional repercussions of punctual mutations and crosstalk among cell signaling will promote the identification of specific combinatorial targeted molecular therapies to specific subsets of patients which will allow the development of personalized-based therapy and increase the survival of patients. Numerous molecular targets are in the cross-road between oncogenic and anti-apoptotic programs, genetic or epigenetic alterations, which overall may have a similar cellular phenotype. The standard antineoplastic chemotherapeutic regimes based on cytotoxic agents leads to significant side effect and modest response rates, marginal changes in natural history, and toxicities that may impact the quality of life of patients. Different strategies involving gene therapy, targeted antibodies or small molecules have been used to regulate cell death/proliferation signals, as well as angiogenesis in liver tumors. In this sense, Sorafenib recently approved for renal cell carcinoma, represents the first tyrosine kinase inhibitor (TKI) licensed for the treatment of patients with advanced HCC. This review summarizes the current status of molecular receptor TKI-based targeted therapy in HCC driving different pathways involved in cell survival, proliferation, migration, angiogenesis and metastasis, which include the regulation of Raf/MEK/ERK, PI3K/Akt/mTOR, and Jak/STAT cell signaling. The study also provides information about cell signaling crosstalk relevant in tyrosine kinase receptors (TKR)-based systemic therapy in HCC.
近年来，肝癌（HCC）中基因组和分子标志物的发现提高了人们对信号转导通路复杂性的认识，以及它们在正常和肝癌细胞中的相关性。确定点突变的功能影响以及细胞信号转导之间的串扰将促进针对特定患者亚组的特定组合靶向分子治疗的识别，从而能够实现基于个体化的治疗并提高患者的生存率。许多分子靶标处于致癌和抗凋亡程序、遗传或表观遗传改变之间的交叉路口，这些改变总体上可能具有相似的细胞表型。基于细胞毒性药物的标准抗肿瘤化学疗法方案会导致严重的副作用和适度的反应率、对自然史的微小改变以及可能影响患者生活质量的毒性。已经使用了涉及基因治疗、靶向抗体或小分子的不同策略来调节细胞死亡/增殖信号以及肝肿瘤中的血管生成。在这方面，最近批准用于肾细胞癌的索拉非尼代表了第一种获准用于治疗晚期 HCC 患者的酪氨酸激酶抑制剂 (TKI)。这篇综述总结了目前 HCC 中基于分子受体 TKI 的靶向治疗的现状，这些治疗针对涉及细胞存活、增殖、迁移、血管生成和转移的不同途径，包括 Raf/MEK/ERK、PI3K/Akt/mTOR 和 Jak/STAT 细胞信号转导的调节。该研究还提供了有关 HCC 中基于酪氨酸激酶受体 (TKR) 的系统治疗中细胞信号转导串扰的信息。
