Mathematical modelling unveils the essential role of cellular phosphatases in the inhibition of RAF-MEK-ERK signalling by sorafenib in hepatocellular carcinoma cells

• Published in: Cancer letters 2017-04, Vol.392, p.1-8
• Main Authors: Saidak, Zuzana, Giacobbi, Anne-Sophie, Louandre, Christophe, Sauzay, Chloé, Mammeri, Youcef, Galmiche, Antoine
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Dual Specificity Phosphatase 1 - metabolism; Dual Specificity Phosphatase 6 - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Hepatocellular carcinoma; Humans; Immunoglobulins; Kinases; Life Sciences; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - pathology; MAP Kinase Kinase Kinases - metabolism; Mathematical modelling; Mathematics; Models, Biological; Mutation; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Ordinary differential equations; Phenylurea Compounds - pharmacology; Phosphatase; Phosphoric Monoester Hydrolases - antagonists & inhibitors; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Phosphatase 2 - metabolism; Protein phosphatases; Proteins; raf Kinases - antagonists & inhibitors; raf Kinases - metabolism; RAF-MEK-ERK cascade; Regulation; Signal transduction; Signal Transduction - drug effects; Sorafenib; Studies; Time Factors; Tumors; Variance analysis; Vascular endothelial growth factor
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.01.038

The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modelling and ordinary differential equations. We analysed the dynamic regulation of the core components of the RAF-MEK-ERK cascade in three human HCC cell lines (Huh7, Hep3B and PLC/PRF5) with heterogeneous responses to sorafenib. In silico predictions derived from our mathematical model suggested that the disappearance of phosphorylated MEK and ERK proteins catalysed by cellular phosphatases is an essential mechanism underlying the anti-ERK efficacy of sorafenib in HCC cells. This prediction was experimentally validated using specific inhibitors of the phosphatases PP2A (Protein Phosphatase 2A) and DUSP1/6 (Dual-specificity phosphatases 1/6). These findings highlight an unexpected mode of action of sorafenib on the kinome of HCC cells, and open new perspectives regarding the therapeutic targeting of the RAF-MEK-ERK cascade in this context. •We modelled the RAF-MEK-ERK pathway in HCC cells exposed to sorafenib.•HCC cells are heterogeneous in their system regulation of the ERK pathway.•DUSP1/6 and PP2A phosphatases are essential for the inhibition of ERK signalling by sorafenib.•Mathematical modelling permits system analysis of oncogenic transduction cascades.