Figure 1. Cross talking between the epidermal growth factor receptor signalling and tumour metabolism pathways in tumour cells.

In cancer cells, EGF or EGF-related ligands bind to EGFR and phosphorylate tyrosine kinase residues, activating three major signal transduction pathways: MAPK, PI3K/Akt and JAK/STAT, which promote cell survival. Upregulated PI3K/Akt activation also stimulates metabolic enzymes (i. e. hexokinase) to drive tumour metabolism. Cancer cells are reliant on mitochondrial metabolism for the increase of glucose to satisfy increased energy requirements. Glucose enters the cell via the glucose transporter (GLUT) to initiate glycolysis. HKII binds to voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT) to form a complex. Thus, the simultaneous inhibition of the EGFR signalling pathway and tumour metabolism pathway was explored. Gefitinib binds to the tyrosine kinase domain of EGFR to inhibit the activation of EGFR signalling whilst PENAO is transported across the plasma membrane and enters the mitochondrial matrix to interact with Cys⁵⁷ and Cys²⁵⁷ residues in the ANT, perturb the mitochondrial permeability transition pore and decrease ATP delivery to the cancer cell.