Hepatocellular carcinoma (HCC) is a major global health problem, which has a grave morbidity and mortality. Over the past few decades, no effective systemic therapeutic modalities have been established for patients with the unresectable HCC in advanced stage. Sorafenib is a small molecule that blocks cancer cell proliferation by targeting the intracellular signaling pathway at the level of Raf-1 and B-Raf serine-threonine kinases, and exerts an anti-angiogenic effect by targeting the vascular endothelial growth factor receptor-1, 2 and 3, and platelet-derived growth factor receptor-beta tyrosine kinases. Recently, two clinical successful applications, SHARP and Asia-Pacific trial, of multikinase inhibitor sorafenib represent a significant advance in the treatment of advanced HCC patients without a curative chance. However, because the results of clinical trials show diverse responses in a subset of HCC patients, a molecular classification of HCC through the excavation of specific biomarkers related to its biological behavior is necessary for sorting HCC patients to each group with a biological homogeneity, ultimately leading to the most suitable individualization of molecular targeted therapy in HCC.
Antineoplastic Agents/therapeutic use ; Benzenesulfonates/therapeutic use ; Carcinoma, Hepatocellular/pathology/secondary/*therapy ; Humans ; Liver Neoplasms/blood supply/pathology/*therapy ; Neovascularization, Pathologic ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-raf/antagonists & inhibitors/metabolism ; Pyridines/therapeutic use ; Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors/metabolism ; Signal Transduction

BRAF is one of the most important pro-oncogenes, which is mutated in approximately 8% of human tumors. The most common BRAF mutation is a valine-to-glutamate transition (V600E) that is expressed primarily in melanoma, colorectal cancer and thyroid carcinoma. MEK/ERK is constitutively activated in the cells expressing BRAFV600E, leading to tumor development, invasion, and metastasis. Therefore, BRAFV600E is a therapeutic target for melanoma and some other BRAFV600E tumors. Vemurafenib, a BRAFV600E inhibitor, which was approved by FDA for the treatment of late-stage melanoma in 2011, produces improved rates of overall and progression-free survival in patients with the BRAFV600E mutation, making a dramatic breakthrough in melanoma treatment. Vemurafenib is also an individual target drug based on genetic diagnosis. However, its therapeutic success is limited by the emergence of drug resistance. Therefore, it is important to explore the mechanisms underlying the resistance for developing new inhibitor drugs and for preventing or delaying the resistance evolution to BRAF inhibitor drugs. In this review, we described the role of BRAFV600E as an anti-tumor drug target and the development of BRAF inhibitors. We also discussed the mechanisms leading to resistance of BRAFV600E inhibitors. Furthermore, therapeutic strategies that might be employed to overcome acquired resistance were proposed.
Animals ; Antineoplastic Agents ; therapeutic use ; Colorectal Neoplasms ; drug therapy ; genetics ; metabolism ; Drug Delivery Systems ; Drug Resistance, Neoplasm ; Humans ; Imidazoles ; therapeutic use ; Indoles ; therapeutic use ; Melanoma ; drug therapy ; genetics ; metabolism ; Mitogen-Activated Protein Kinase Kinases ; metabolism ; Mutation ; Oximes ; therapeutic use ; Proto-Oncogene Proteins B-raf ; antagonists & inhibitors ; genetics ; metabolism ; Sulfonamides ; therapeutic use ; Thyroid Neoplasms ; drug therapy ; genetics ; metabolism

BACKGROUND/AIMS: 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a cellular energy sensor that monitors intracellular AMP/adenosine triphosphate (ATP) ratios and is a key regulator of the proliferation and survival of diverse malignant cell types. In the present study, we investigated the effect of activating AMPK by 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR) in thyroid cancer cells. METHODS: We used FRO thyroid cancer cells harboring the BRAF(V600E) mutation to examine the effect of AICAR on cell proliferation and cell survival. We also evaluated the involvement of mitogen-activated protein kinase (MAPK) pathways in this effect. RESULTS: We found that AICAR treatment promoted AMPK activation and suppressed cell proliferation and survival by inducing p21 accumulation and activating caspase-3. AICAR significantly induced activation of p38 MAPK, and pretreatment with SB203580, a specific inhibitor of the p38 MAPK pathway, partially but significantly rescued cell survival. Furthermore, small interfering RNA targeting AMPK-alpha1 abolished AICAR-induced activation of p38 MAPK, p21 accumulation, and activation of caspase-3. CONCLUSIONS: Our findings demonstrate that AMPK activation using AICAR inhibited cell proliferation and survival by activating p38 MAPK and proapoptotic molecules in FRO thyroid cancer cells. These results suggest that the AMPK and p38 MAPK signaling pathways may be useful therapeutic targets to treat thyroid cancer.
AMP-Activated Protein Kinases/genetics/metabolism ; Aminoimidazole Carboxamide/*analogs & derivatives/pharmacology ; Antineoplastic Agents/*pharmacology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Enzyme Activators/pharmacology ; Humans ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/genetics ; RNA Interference ; Ribonucleotides/*pharmacology ; Signal Transduction/*drug effects ; Thyroid Neoplasms/*enzymology/genetics/pathology ; Time Factors ; Transfection ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism

Adenocarcinoma ; diagnosis ; drug therapy ; genetics ; metabolism ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; diagnosis ; drug therapy ; genetics ; metabolism ; Carcinoma, Squamous Cell ; diagnosis ; drug therapy ; genetics ; metabolism ; DNA-Binding Proteins ; genetics ; metabolism ; Discoidin Domain Receptors ; Glutamates ; therapeutic use ; Guanine ; analogs & derivatives ; therapeutic use ; Humans ; Lung Neoplasms ; diagnosis ; drug therapy ; genetics ; metabolism ; Molecular Diagnostic Techniques ; methods ; Mutation ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Pemetrexed ; Protein Kinase Inhibitors ; therapeutic use ; Proto-Oncogene Proteins B-raf ; genetics ; metabolism ; Receptor Protein-Tyrosine Kinases ; genetics ; metabolism ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; genetics ; metabolism ; Receptors, Mitogen ; genetics ; metabolism ; Transcription Factors