The underlying cause for resistance was eventually decided to be caused by secondary mutations as observed in the Abl KD (Shah et al

The underlying cause for resistance was eventually decided to be caused by secondary mutations as observed in the Abl KD (Shah et al., 2002). Bcr-Abl, led to the generation of several drugs including imatinib, dasatinib and sunitinib that provided a rich understanding of this phenomenon. It became clear that mutations alone were not the only cause of resistance. Additional mechanisms were involved, including alternative splicing, alternative/compensatory signaling pathways and epigenetic changes. This review will focus on resistance to tyrosine kinase inhibitors (TKIs), receptor TK Evodiamine (Isoevodiamine) (RTK)-directed antibodies and antibodies that inactivate specific RTK ligands. New approaches 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 evolution of KD mutations in TKIs is 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 that they typically have no effect on Evodiamine (Isoevodiamine) kinase activity. Plxna1 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 note, 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 Evodiamine (Isoevodiamine) (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 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 cancer cells. A key family of RTKs in tumorigenesis and therapeutic strategies in multiple cancer 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 to the avian viral erythroblastosis oncogene), is comprised of four members HER1-4 or ErbB1-4. Ligand binding leads to a conformational change 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. The phosphorylated receptor dimer, through interactions of its phosphotyrosines, binds to effectors containing Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains activating downstream pathways (Roskoski, 2014) including Ras-MAPK (Erk), PI3K/Akt and STAT activation downstream of the JAK non-receptor tyrosine kinase. Of note, activation of the IGF-1R can result in receptor cross-talk as a result to protease activation and the shedding of membrane-tethered EGFR ligands. Alternatively, activation of the HIF-1 transcription factor resulting in VEGF expression and.