(erlotinib, gefitinib or antibodies suchOncotarget 2012; 3: 236-as cetuximab). In some cases resistance to either Raf/ MEK or PI3K may occur as some upstream mutations (e.g., EGFR mutations) activate both Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. Treatment of cells with Ras mutations with certain mutant allele selective B-Raf inhibitors can result in Raf-1 activation. Dominant negative B-Raf mutations can still bind and activate Raf-1 if the cell has a mutant Ras allele. Finally some B-Raf inhibitor resistant cells overexpress various critical cell cycle regulatory molecules such as cyclin D. The various mechanisms of inhibitor resistance involving other components in these Quinagolide (hydrochloride) supplier pathways are explained in more detail in McCubrey et al. [17]. Many recent studies are directed at increasing cancer patient survival by targeting these and other pathways in cancer cells. Illustrations of the most important receptors and intracellular molecular signaling pathways, as well as sites of intervention with small molecule inhibitors and monoclonal antibodies are presented in Figures 1-2. Certain molecular-targeted agents are actually promiscuous (e.g. sorafenib, regorafenib, sunitinib, brivanib and others), i.e. they simultaneously target more than one molecule and this multiple targeting could enhance their therapeutic efficacy, while others act on a single target (e.g. AZD6244, AZD8055, everolimus andothers) (Figure 1).EGF/EGFR PATHWAYThe EGFR (also known as ErbB1 and Her1) belongs to the ERB family of receptor tyrosine kinases (RTKs), which includes ErbB2 (also known as Her2), ErbB3 (also known as Her3) and ErbB4 (also known as Her4). The members are all endowed with tyrosine kinase (TK) activity, with the exception of ErbB3. All members share a common structure, showing an extracellular ligand-binding domain, a transmembrane domain and an intracellular domain where the tyrosine kinase VP 63843MedChemExpress VP 63843 activity resides. EGFR forms homo- or heterodimers upon ligand binding. Dimerization results in auto-phosphorylation of EGFR with the subsequent activation of a number of downstream signaling pathways, including the PI3K/Akt/ mTOR and the Ras/Raf/MEK/ERK pathways (Figure 2). With the exception of ErbB2, which has no ligand, all the other members can bind a family of growth factors. Ligands for EGFR are EGF, TGF-, epigenin (EPG), amphiregulin (AREG), heparin-binding-EGF (HB-EGF), epirugulin (EREG) and -cellulin (BTC) and the last three ligands are also able to bind to ErbB4/Her4. TheFigure 1: Relevant receptors and corresponding molecular targeted agents currently tested in preclinical and clinical HCC trials.AMG386 Bevacizumab Cetuximab Ramucirumab Cixutumumab AVE1642 BIIB022 MEDI-AngEGFVEGF PDGFIGF FGFSCFHGFEGF-RErlotinib Lapatinib GefitinibVEGF-RSorafenib Regorafenib Brivanib Linifanib Cediranib Sunitinib BIBF1120 Pazopanib E7080 TSU-68 Vandetanib Dovitinib Foretinib XL184 AZDPDGF-RSorafenib Regorafenib Linifanib Cediranib Sunitinib BIBF1120 Pazopanib TSU-68 Vandetanib Dovitinib AZDFGF-RBrivanib BIBF1120 E7080 TSU-IGF-IROSI-TieRegorafenibc-KitSunitinib AZD2171 Pazopanibc-MetARQ197 Foretinibwww.impactjournals.com/oncotargetOncotarget 2012; 3: 236-neuregulin (NRG) ligands NRG-1 and NGR-2 bind to both ErbB3/Her3 and ErbB4/Her4, whereas NGR-3 and NGR-4 only recognize ErbB4/Her4. The receptor most studied in HCC is EGFR/ ErbB1. The rationale for targeting the EGFR pathway comes from the following observations: there is a high frequency of EGFR overexpression in.(erlotinib, gefitinib or antibodies suchOncotarget 2012; 3: 236-as cetuximab). In some cases resistance to either Raf/ MEK or PI3K may occur as some upstream mutations (e.g., EGFR mutations) activate both Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. Treatment of cells with Ras mutations with certain mutant allele selective B-Raf inhibitors can result in Raf-1 activation. Dominant negative B-Raf mutations can still bind and activate Raf-1 if the cell has a mutant Ras allele. Finally some B-Raf inhibitor resistant cells overexpress various critical cell cycle regulatory molecules such as cyclin D. The various mechanisms of inhibitor resistance involving other components in these pathways are explained in more detail in McCubrey et al. [17]. Many recent studies are directed at increasing cancer patient survival by targeting these and other pathways in cancer cells. Illustrations of the most important receptors and intracellular molecular signaling pathways, as well as sites of intervention with small molecule inhibitors and monoclonal antibodies are presented in Figures 1-2. Certain molecular-targeted agents are actually promiscuous (e.g. sorafenib, regorafenib, sunitinib, brivanib and others), i.e. they simultaneously target more than one molecule and this multiple targeting could enhance their therapeutic efficacy, while others act on a single target (e.g. AZD6244, AZD8055, everolimus andothers) (Figure 1).EGF/EGFR PATHWAYThe EGFR (also known as ErbB1 and Her1) belongs to the ERB family of receptor tyrosine kinases (RTKs), which includes ErbB2 (also known as Her2), ErbB3 (also known as Her3) and ErbB4 (also known as Her4). The members are all endowed with tyrosine kinase (TK) activity, with the exception of ErbB3. All members share a common structure, showing an extracellular ligand-binding domain, a transmembrane domain and an intracellular domain where the tyrosine kinase activity resides. EGFR forms homo- or heterodimers upon ligand binding. Dimerization results in auto-phosphorylation of EGFR with the subsequent activation of a number of downstream signaling pathways, including the PI3K/Akt/ mTOR and the Ras/Raf/MEK/ERK pathways (Figure 2). With the exception of ErbB2, which has no ligand, all the other members can bind a family of growth factors. Ligands for EGFR are EGF, TGF-, epigenin (EPG), amphiregulin (AREG), heparin-binding-EGF (HB-EGF), epirugulin (EREG) and -cellulin (BTC) and the last three ligands are also able to bind to ErbB4/Her4. TheFigure 1: Relevant receptors and corresponding molecular targeted agents currently tested in preclinical and clinical HCC trials.AMG386 Bevacizumab Cetuximab Ramucirumab Cixutumumab AVE1642 BIIB022 MEDI-AngEGFVEGF PDGFIGF FGFSCFHGFEGF-RErlotinib Lapatinib GefitinibVEGF-RSorafenib Regorafenib Brivanib Linifanib Cediranib Sunitinib BIBF1120 Pazopanib E7080 TSU-68 Vandetanib Dovitinib Foretinib XL184 AZDPDGF-RSorafenib Regorafenib Linifanib Cediranib Sunitinib BIBF1120 Pazopanib TSU-68 Vandetanib Dovitinib AZDFGF-RBrivanib BIBF1120 E7080 TSU-IGF-IROSI-TieRegorafenibc-KitSunitinib AZD2171 Pazopanibc-MetARQ197 Foretinibwww.impactjournals.com/oncotargetOncotarget 2012; 3: 236-neuregulin (NRG) ligands NRG-1 and NGR-2 bind to both ErbB3/Her3 and ErbB4/Her4, whereas NGR-3 and NGR-4 only recognize ErbB4/Her4. The receptor most studied in HCC is EGFR/ ErbB1. The rationale for targeting the EGFR pathway comes from the following observations: there is a high frequency of EGFR overexpression in.