Prepared by: Alaa M ElGohary

* Signaling pathways in hepatocellular

carcinoma

*Signaling pathways

* A more complete understanding of the genetic alterations in HCC could have a major impact on the development of new treatment strategies.

* There is high complexity and heterogeneity of HCC cancer genomes.

* Signaling pathways frequently deregulated in HCC.

Proliferation signaling pathways

Epidermal growth factor (EGF) signaling:

oEGF is a growth factor that stimulates cell growth, proliferation, and differentiation by binding to its receptor EGFR.

EGF was ranked among the top up-regulated genes included in a gene signature that was able to identify HCC patients treated with surgical resection at high risk of developing a late recurrence.

an EGFR tyrosine kinase inhibitor, was able to significantlydecrease HCC incidence in a genotoxic model of HCC.

*EGFR signaling pathways. Ligand binding to EGFR leads to receptor dimerization. Subsequently, downstream pathways, including the MAPK pathway (through RAS) and the PI3K pathway (through p110 and subsequently PIP3), are activated. In the PI3K pathway, PIP3 activates AKT by facilitating its phosphorylation by PDPK1 and PDPK2 (mtorC2). AKT, in turn, activates mTOR. PTEN regulates activity of the PI3K pathway by converting PIP3 back to PIP2. In the MAPK pathway, RAS, RAF, MEK, and ERK are activated by sequential kinase activity. Both the pathways regulate multiple cellular processes vital for the malignant cell. Ligand binding and, therefore, downstream activation are blocked by EGFR MoAb. The most common aberrations leading to inappropriate activation of the pathways in cancer cells are also depicted

oThe insulin-like growth factor (IGF) signaling

oare proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "axis") consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (Insulin-like growth factor 1 (IGF-1) and Insulin-like growth factor 2 (IGF-2)), a family of six high-affinity IGF-binding proteins (IGFBP-1 to IGFBP-6)

oIn HCC, the most frequently described aberrant feature concerning this pathway is over-expression of IGF2,even found in pre-neoplastic lesions

oIGF2, highly expressed during embryonic development, is strongly down-regulated after birth. Reactivation of IGF2 expression involves loss of specific imprinting and hypo methylation

oHepatocyte growth factor (HGF)

oThe unique ligand for the MET receptor. MET activation by HGF induces disruption of intercellular links and allows cells to migrate from their primary location to adjacent surroundings.

oThe HGF/MET system is a major player of cell migration during embryogenesis and recent data has shown that the HGF/MET system is involved in reactivation of the ‘‘invasive program” during tumor progression and metastasis

oA study found a correlation between MET over-expression and a higher incidence of intrahepatic metastases, as well as a reduced survival following tumor resection.

oMesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR), is a tyrosine kinase receptor that plays an imperative role in angiogenesis and tumor growth. Similar to its role in normal tissue, c-Met deregulation enhances tumor cell proliferation, survival, motility and invasion leading to metastasis. The mechanism of inappropriate signaling is through mutation, overexpression, ligand binding or interaction with other cell surface receptors.

oAmplification of c-met has been shown to cause resistance to treatment with EGFR family inhibitors.

oXcovery’s X-379 is an oral, potent and selective inhibitor of c-Met autophosphorylation. X-379 is potent against most c-Met mutations and is able to completely inhibitor c-Met at tolerable doses. It is expected that X-379 will be broadly active in human tumors, particularly in combination with other tyrosine kinase inhibitors for which resistance develops as a function of c-met activation.

oAt least three routes of pathway intervention have been followed as selective anticancer drug development strategies:

oAntagonism of ligand binding, oInhibition of TK catalytic function,

oBlockade of interactions between activated receptors and downstream intracellular effectors.

*Reference:Lars Zender, Augusto Villanueva, Victoria Tovar, Daniela Sia, Derek Y. Chiang,Josep M. Llovet. Cancer gene discovery in hepatocellular carcinoma. journal of hepatology 2010