Signalling: Survival of the sweetest

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EGFR promotes cell survival in a kinase-independent fashion by preventing autophagy and maintaining a basal level of intracellular glucose, thus explaining the disappointing response rates to EGFR inhibitors in cancer patients.

Response rates to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in cancer treatment have been surprisingly and disappointingly low. Zhang Weihua and colleagues now shed some light on this issue by revealing a kinase-independent function of EGFR in maintaining cell survival.


BRANDX

Using prostate, breast and colon cancer cells the authors 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.

So, how does EGFR maintain intracellular glucose levels? Data indicate that EGFR expression can alter glucose uptake, and the authors also found that expression of the sodium and glucose cotransporter SGLT1 was undetectable in cells treated with EGFR siRNA compared with controls. Moreover, knockdown of SGLT1 directly mimicked EGFR siRNA-mediated autophagy. Downregulation of SGLT1 in the absence of EGFR could be rescued by inhibiting proteasome activity, implying that SGLT1 is degraded in response to the loss of EGFR expression. Importantly, SGLT1 was found to interact with wild-type and a kinase-deficient EGFR, and SGLT1 levels were preserved in cells transfected with EGFR siRNA and siRNA-resistant wild-type or kinase-deficient EGFR constructs. These findings suggest that EGFR stabilizes SGLT1 independently of its kinase activity.

Finally, the authors tested the glucose starvation sensitivity of cancer cells expressing varying levels of EGFR. Cancer cells that express EGFR also expressed SGLT1 and were resistant to glucose starvation-induced cell death. Conversely, cancer cells lacking EGFR did not express SGLT1 and could not survive in physiological glucose concentrations, although overexpression of EGFR or SGLT1 enhanced their survival even in low glucose.

This study reveals 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.

Katharine H. Wrighton

References

Weihua, Z. et al. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 13, 385–393 (2008) | Article | PubMed |
Sharma, S. V., Bell, D. W., Settleman, J. & Haber D. A. Epidermal growth factor receptor mutations in lung cancer. Nature Rev. Cancer 7, 169–181 (2007) | Article | PubMed |