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

May 05, 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

Explore further: Generation of tanners see spike in deadly melanoma

add to favorites email to friend print save as pdf

Related Stories

Huge waves measured for first time in Arctic Ocean

3 hours ago

As the climate warms and sea ice retreats, the North is changing. An ice-covered expanse now has a season of increasingly open water which is predicted to extend across the whole Arctic Ocean before the middle ...

Underwater elephants

3 hours ago

In the high-tech world of science, researchers sometimes need to get back to basics. UC Santa Barbara's Douglas McCauley did just that to study the impacts of the bumphead parrotfish (Bolbometopon muricatum) on cor ...

Recommended for you

Generation of tanners see spike in deadly melanoma

8 hours ago

(AP)—Stop sunbathing and using indoor tanning beds, the acting U.S. surgeon general warned in a report released Tuesday that cites an alarming 200 percent jump in deadly melanoma cases since 1973.

Penn team makes cancer glow to improve surgical outcomes

9 hours ago

The best way to cure most cases of cancer is to surgically remove the tumor. The Achilles heel of this approach, however, is that the surgeon may fail to extract the entire tumor, leading to a local recurrence.

Cancer: Tumors absorb sugar for mobility

21 hours ago

Cancer cells are gluttons. We have long known that they monopolize large amounts of sugar. More recently, it became clear that some tumor cells are also characterized by a series of features such as mobility or unlikeliness ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

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.