fig1

Figure 1. Signaling pathways involved in the development of resistance to Human epidermal growth factor receptor 2 (Her2)-targeted therapy. A central element of resistance appears to be PI3K/AKT/mTOR signaling, which may demonstrate persistent activation through c-MET, IGF-1, p-Src, or interference with PTEN and PP2A mediated suppression of mTOR and downstream signaling at the level of p70S6K and 4EBP1. PP2A activity could also be inhibited by EZH2-mediated slicing of the PP2A regulatory B-subunit. miRNAs and p-Src can also promote the loss of PTEN activity. Resistance could also be mediated through c-MET or IGF1 activation of the RAS/MAPK signaling pathway well as IGF-1; IGF1 can also induce Her2 receptor phosphorylation. p27^Kip1 expression is reduced via SCF^SKP E3 ubiquitin-mediated degradation, which can be augmented by IGF-1 or via miRNAs which are overexpressed through p-Src, causing loss of cyclin E/CDK2 control and promoting cell cycle progression. CD36 contributed to tumor growth and resistance to Her 2 targeted therapies by providing FAs as a critical energy source for tumorigenesis. PTEN: Phosphatase and tensin homolog; IGF: insulin-like growth factor; MAPK: mitogen-activated protein kinase; FAs: fatty acids.