Prognosis for many epithelial tumors correlates with the expression level of epidermal growth factor receptor. “It has traditionally been thought that tumor cells with too much receptor have too much tyrosine kinase activity,” Hung says. “But therapeutic kinase blockade has been only partially successful.”
Investigating other mechanisms, the authors showed that knockdown of EGFR reduced intracellular glucose levels, and increased production of energy-scavenging autophagosomes, ultimately leading to cell death. This cell death could be prevented by providing extra glucose.
This effect on cellular glucose is due to an interaction between EGFR and the sodium/glucose cotransporter, SGLT1, the team found. EGFR knockdown reduced expression of SGLT1, and SGLT1 knockdown caused autophagosome-induced death. Transporter loss was not due to lowered transcription, suggesting that the protein became unstable in the absence of EGFR. EGFR's stabilizing effect was dependent on its extracellular domain and remained even in the absence of its kinase activity.
“The excess stabilization of the glucose transporter allows these cells to survive in harsher conditions,” Hung says. Targeting this additional function of EGFR might therefore make for a better therapy.