Wednesday, July 2, 2008

What's stopping EGFR inhibitors from being more effective?

Response rates with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in cancer treatment have been low. However, a recent study may have shed some light by revealing a kinase-independent function of EGFR in maintaining cell survival.

Mediating RNA interference in cultured mammali...Image via Wikipedia
Using prostate, breast and colon cancer cells, it was demonstrated that small interfering RNA (siRNA)-mediated knockdown of EGFR, but not inhibition of EGFR kinase activity, leads to autophagic cell death. Autophagy can occur when external energy sources are low or unobtainable and, although glucose levels remained constant in cells treated with kinase inhibitors, they were decreased by around 50% in cells transfected with EGFR siRNA.

The study found that EGFR–SGLT1 may confer a survival advantage to cancer cells by maintaining a basal level of intracellular glucose and preventing autophagy. This may help to explain previous data indicating that inhibition of EGFR kinase activity is not sufficient to induce cell death, or to negate all of the functions of EGFR.

Targeting both kinase-dependent and kinase-independent functions of EGFR may be necessary for more successful therapy in the future.


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