EGFR protects cancer cells from starvation via a kinase-independent mechanism

May 5, 2008

Scientists have uncovered a previously unrealized mechanism by which the epidermal growth factor receptor (EGFR), a tyrosine kinase, promotes survival of cancer cells through a kinase-independent mechanism. The research, published by Cell Press in the May issue of the journal Cancer Cell, provides a rationale for the less than impressive results of recent clinical trials aimed solely at interfering with kinase activity and suggests new directions for potential therapeutic strategies.

The EGFR is closely associated with cell proliferation and survival and excessive expression, and activation of the EGFR is often observed in cancers of epithelial origin. Until now, it was believed that most of EGFR’s functions were mediated by its kinase activity, and several compounds that specifically inhibit the kinase activity of the EGFR were developed with the aim of treating these cancers.

However, the clinical experience so far has been that blockade of the EGFR tyrosine kinase activity alone does not elicit significant clinical outcomes in most patients.

“The expression level of EGFR in cancer tissues is correlated with prognosis, but not with responsiveness to EGFR tyrosine kinase inhibitor treatment, suggesting that, independent of its kinase activity, EGFR may contribute to the progression of cancer,” explains study author Dr. Isaiah J. Fidler from the Department of Cancer Biology at The University of Texas M.D. Anderson Cancer Center. Dr. Fidler and colleagues designed a series of studies to investigate the kinase-independent prosurvival function of the EGFR in cancer cells.

The researchers found that the EGFR enables human cancer cells to maintain adequate intracellular glucose levels by stabilizing the sodium/glucose transporter 1 (SGLT1) via a kinase-independent mechanism. Glucose is a major energy substrate for all cells, and without appropriate amounts, cells essentially starve to death through a process called autophagic cell death. Cancer cells are very active metabolically and consume more glucose than normal tissues; moreover, the EGFR overexpression and the associated enhanced stability of SGLT1 allow tumor cells to survive under conditions that would be less than optimal, even for normal cells.

“Our results suggest that EGFR, independent of its kinase activity, maintains the basal intracellular glucose level and thereby prevents cancer cells from succumbing to autophagic death. It is possible that this function of the EGFR may even increase the survival capacity of cancer cells in the presence of chemotherapeutic agents,” offers study author Dr. Mien-Chie Hung. The researchers suggest that inhibition of both EGFR-mediated SGLT1 stabilization and EGFR kinase activity may be necessary for eradication of epithelial tumors.

Source: Cell Press

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gdpawel
not rated yet May 08, 2008
Measuring the net effect of all processes versus individual molecular targets

That is why EGF-targeted (or VEGF-targeted) drugs are poorly-predicted by measuring the preferred target EGFR (or VEGF). They can be well-predicted by measuring the effect of the drugs on the function of live cells.

There are many pathways to the altered cellular (forest) function, hence all the different %u201Ctrees%u201D which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

Many of these drugs cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond.

You still need to measure the net effect of all processes, not just the individual molecular targets.

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