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.