fig2
Figure 2. Mechanism of resistance to lapatinib. Myriad potential mechanisms of resistance to lapatinib have been reported. (1) Alterations in cell death cascade through up-regulation of XIAP, which blocks caspase 3-mediated apoptosis. (2) MCL-2 hyperactivation or TRAIL receptor can further attenuate apoptosis functions. (3) Activation of compensatory pathways may be mediated by up-regulation of RTKs, such as HER3, through the formation of HER2/HER3 heterodimerization; MET, the phosphorylation of which is stimulated by HGF; AXL overexpression; and IGF-IR dimerization. These receptors can dimerize with HER2 to further promote proliferative cues. (4) Activation of β1-integris can further promote activation of Src or PI3K/Akt/mTOR signaling axis to enhance cell proliferation. (5) Components of the PI3K/Akt/mTOR pathway, Src family kinases, and PTK6 may dampen pro-apoptotic function and enhance cell proliferation. (6 and 7) HSF1 and mTOR can mediate cancer cell survival and metastasis. (8) Modulation of ER increase cell proliferation. Images were created using Biorender.com. Casp 3: caspase 3; Casp 8: caspase 8; Casp 9: caspase 9; CDK 4/6: cyclin-dependent kinase4/6; Cyto C: cytochrome C; EGFR: epidermal growth factor receptor; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor 3; IGF-1R: insulin-like growth factor 1 receptor; MCF-1: myeloid leukemia 1; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; Rb: retinoblastoma protein; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand, XIAP: X inhibitor of apoptosis protein; RTKs: receptor tyrosine kinases; HGF: hepatocyte growth factor; PTK6: protein tyrosine kinase 6; MAPK: mitogen activated protein kinase; MCL: mantle cell lymphoma; MET: tyrosine-protein kinase MET; AXL: AXL receptor tyrosine kinase; IGF-IR: insulin-like growth factor receptor 1; BCL-XL: b-cell lymphoma extra-large; HSF1: Heat shock factor 1; NFκB: nuclear factor kappa-beta; ERK: extracellular signal-regulated kinase
