Role of De Novo Fatty Acid Synthesis in Intrinsic Activation of EGFR in Cancer

De novo fatty acid synthesis is one of the major upregulated metabolic pathways in cancer. De novo fatty acid synthesis pathway is crucially involved in cell proliferation, survival and drug resistance of cancer cells. This study focused on the role of fatty acid synthesis in intrinsic activation of EGFR and drug resistance in cancer. EGFR is a receptor tyrosine kinase expressed in most human cancers of epithelial origin and advanced cancers. Besides the plasma membranous (pmEGFR) and nuclear localization, EGFR can also exist in mitochondria (mtEGFR). Our studies revealed that EGFR exists in the inner mitochondrial membrane of prostate and breast cancer cells and promotes mitochondrial fusion through increasing the protein levels of PHB2 and OPA1. Interestingly, in this study, we found that activated pmEGFR activates mtEGFR through de novo synthesized palmitate, through palmitoylation, and promotes mitochondrial fusion. Along with mtEGFR, we also found that pmEGFR also undergo de novo fatty acid synthesis dependent palmitoylation which is important for EGFR localization, stability and signaling. We also observed intrinsic activation of EGFR in response to anticancer drugs such as SN38 and oxaliplatin dependent on de novo fatty acid synthesis. Finally, targeting de novo fatty acid synthesis or palmitoylation significantly increased the sensitivity of cancer cells to EGFR TKIs or anticancer drugs. In conclusion, through this study we’ve uncovered the importance of de novo fatty acid synthesis in intrinsic activation and non-classical functions of EGFR in cancer.