In ErbB2 amplified cells, the principal signaling unit is comprised of ErbB2/ErbB3/phosphoinositide 3-kinase (PI3K) complexes leading to Akt activation (Junttila et al

In ErbB2 amplified cells, the principal signaling unit is comprised of ErbB2/ErbB3/phosphoinositide 3-kinase (PI3K) complexes leading to Akt activation (Junttila et al., 2009). pathways and epigenetic changes. This review will focus FBXW7 on resistance to tyrosine kinase inhibitors (TKIs), receptor TK (RTK)-directed antibodies and antibodies that inactivate specific RTK ligands. New methods and concepts aimed at avoiding the generation of drug resistance will be examined. Many RTKs, including the IGF-1R, are dependence receptors that induce ligand-independent apoptosis. How this this signaling paradigm has implications on therapeutic strategies will also be considered. and sensitivity to dasatinib and nilotinib; these analyses have been reviewed elsewhere (Thomas O’Hare et al., 2007). The natural development of KD mutations in TKIs is usually typified by the T315I mutation in Abl, a key contact site for imatinib. T315I represents mutation of the “gatekeeper” residue in Abl and results in conferring resistance to the Abl inhibitors, imatinib, dasatinib and nilotinib (Barouch-Bentov & Sauer, 2011). A key feature of gatekeeper mutations such as T315I in Abl is usually that they typically have no effect on kinase activity. Rather, they block TKI access to the hydrophobic pocket within the activation loop via steric hindrance which, in turn, blocks inhibitor binding via loss of the necessary hydrogen bonding required to form a stable enzyme-inhibitor complex (Zhang, Yang, & Gray, 2009). Additional point mutations located within the ATP binding loop prevent Abl from assuming a high affinity conformation capable of binding imatinib. Activation loop mutations are thought to stabilize the active conformation, which imatinib is unable to bind. Of notice, a number of activation loop mutations were inhibitable with the second generation Bcr-Abl kinase inhibitors such as nilotinib (Weisberg et al., 2005) and dasatinib, a dual Src/Abl inhibitor (Shah et al., 2004), as a result of their increased affinity for Abl kinase compared to imatinib. Dasatinib has a 300-fold greater potency than imatinib and it binds to the catalytically active conformation of Abl, further enabling its ability to inhibit imatinib-resistant mutants (Shah et al., 2004). In differentiating between intrinsic and acquired resistance, Zhang et al., raise the issue that gatekeeper mutations may be pre-existing rather than acquired (Zhang et al., 2009). The point mutations identified in the Bcr-Abl KD result in resistance to imatinib as a result of reduced KD flexibility, limiting its ability to form an inactive conformation necessary for imatinib binding and inhibition (Burgess, Skaggs, Shah, Lee, & Sawyers, 2005). On this basis, second generation inhibitors were developed with the goal of increased potency above that of imatinib. Indeed, mutations found to be resistant to dasatinib are present within contact sites (Burgess et al., 2005) while nilotinib-induced point mutations were also resistant to imatinib. (Ray, Cowan-Jacob, Manley, Mestan, & Griffin, 2007). In contrast, induction of imatinib resistance is often associated with Bcr-Abl mRNA and protein overexpression, which is usually not always associated with gene amplification. Elevated P-glycoprotein expression and multidrug resistance-based drug efflux, as seen with many chemotherapeutics, has also been observed for imatinib (Mahon et al., 2000), and the activation of integrin and/or growth factor receptor signaling pathways have been described as mechanisms responsible for imatinib refractoriness (Deininger et al., 2005). Receptor and non-receptor tyrosine kinases activate common pathways Receptor and non-receptor tyrosine kinases utilize a variety of common effector proteins and pathways to mediate their downstream effects in normal cells and malignancy cells. A SB290157 trifluoroacetate key family of RTKs in tumorigenesis and therapeutic strategies in multiple SB290157 trifluoroacetate malignancy sites is the epidermal growth factor receptor (EGFR) also referred to as HER1 (human epidermal growth factor receptor1) or ErbB1 family (based on their relatedness SB290157 trifluoroacetate to the avian viral erythroblastosis oncogene), is usually comprised of four users HER1-4 or ErbB1-4. Ligand binding leads to a conformational switch in the 3D structure of the EGFR, its increased lateral mobility in the plasma membrane, homo- or heterodimerization and transphosphorylation of its partnering receptor’s intracellular domain name. The phosphorylated receptor dimer, through interactions of its phosphotyrosines, binds to effectors made up of Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains activating downstream pathways (Roskoski, 2014) including Ras-MAPK (Erk), PI3K/Akt and STAT.