Everolimus overcomes resistance to EGFR inhibitors

April 9, 2008

NEW YORK (Reuters Health) - Inhibition of the mammalian target of rapamycin (mTOR) pathway by everolimus works in concert with epithelial growth factor receptor (EGFR) inhibitors in human tumors both sensitive and resistant to anti-EGFR drugs, according to Italian researchers.

"Given the emerging role of mTOR inhibitors," senior investigator Dr. Giampaolo Tortora told Reuters Health, "the novelty of our study is that not only does everolimus have a potent cooperative effect with EGFR inhibitors ... but, intriguingly, it is able to reverse the resistance to EGFR inhibitors in tumors resistant to these agents."

In the March issue of the British Journal of Cancer, Dr. Tortora of the University of Naples and colleagues note that mTOR has been implicated in resistance to EGFR inhibitors.

To evaluate the effect of mTOR blockade with everolimus, with and without anti-EGFR drugs including gefitinib, the researchers conducted a series of studies on human cancer cells in vitro and in mice with xenografts.

Everolimus partially restored sensitivity to gefitinib and cetuximab in resistant cancer cell lines. The researchers also found that everolimus inhibited VEGF-stimulated capillary tube and network formation, as did gefitinib. The combination almost suppressed this process.

There were similar findings in mice with gefitinib-resistant and -susceptible colon cancer xenografts. As might be expected, gefitinib alone was not effective against resistant tumors. However, after 56 days, the combination prompted a more than 90% inhibition of the growth of both types of tumor.

The observation that mTOR inhibition seems to reverse resistance, concluded Dr. Tortora, "opens a new potential perspective for mTOR inhibitors in the clinics and, interestingly, implies other yet undisclosed mechanisms linking mTOR to EGFR signaling."