EGFR kinase inhibitors are big business. And from the looks of some recently published studies, they may become bigger business still.
In normal cells, the EGFR tyrosine kinase is activated when growth factors bind to its receptor. Many cancer cells, though, have mutations that render the kinase permanently active, leading to uncontrolled cell division.
Multiple approved therapeutics try to interfere with this hyperactivity. Some, such as trastuzumab (Herceptin, Genentech Inc.) cetuximab (Erbitux, ImClone Systems Inc.), and the most recent addition to the arsenal, Amgen's panitumumab (Vectibix), target the receptors to prevent them from activating the kinase that is attached to them. Erlotinib (Tarceva, OSI Pharmaceuticals Inc., Genentech Inc.) jams the active site of the kinase itself.
Two recent papers report on another indication for EGFR tyrosine kinase inhibitors, and an additional point in the EGFR pathway that could be a promising target.
In a study published online before print in the Journal of Clinical Investigation Jan. 11, researchers from Lawrence Berkeley Laboratory in Berkeley, Calif. report that by inhibiting the sheddase ADAM-17, which is upstream of EGFR, they could prevent amphiregulin and TGF-alpha, two ligands of the EGF receptor, from being released from the extracellular matrix.
In breast cancer cells grown in a three-dimensional culture system designed to mimic the tumor cell microenvironment, inhibiting ADAM-17 (which the researchers call by its other name, TACE) "results in the reversion of the malignant phenotype of these breast cancer cells and switches their behavior back to a phenotype very reminiscent of non-malignant breast epithelial cells." said first author Paraic Kenny, postdoctoral researcher in the Life sciences division of LBL.
"We have designed an entirely new way of targeting EGFR signaling in breast cancer," he added. "Almost all the work to date has involved the use of antibodies that stick to kinases or drugs that block kinase activities."
The work extends a study published earlier this year by Wilmington, Del.-based Incyte Corp. showing that inhibiting ADAM-17 blocked the release of the EGFR ligand heregulin from the cell membrane, increased sensitivity to a tyrosine kinase inhibitor in cell culture and showed antitumor activity in a xenograft model. Incyte is in clinical trials testing sheddase inhibitors as breast cancer therapeutics.
The findings come a month after a paper in PLoS Medicine reported on EGFR mutations in patients with the brain tumor glioblastoma that affected not the kinase itself, but the extracellular domain of the receptor.
The researchers, who hail from Harvard Medical School, the University of California at Los Angeles and San Francisco, and Johns Hopkins University in Baltimore, sequenced the complete EGFR coding sequence in both glioblastoma tumor samples and cell lines.
They found mutations in the receptor sequences of roughly one-eighth of their samples. While lung cancer patients tend to have mutations in the kinase itself, the authors of the PLoS paper found a mutated kinase in only one of about 150 samples. The researchers confirmed that the receptor mutations led to increased activity of the tyrosine kinase and cancerous cell growth in culture experiments. In culture, cells with mutations in the extracellular receptor sequence were sensitive to Tarceva.
While the extracellular mutations theoretically could be targeted directly by yet-to-be-developed pharmaceuticals, the fact that they respond to Tarceva suggests that their main value may lie in determining which glioblastoma patients can benefit from such treatments.
Because the mutations are in a different part of the EGFR-tyrosine kinase system than in lung cancer patients, PLoS Medicine scientific editor Andrew Lassmann explained in his summary of the results that "Until now researchers have concentrated on the kinase domain of this and other receptor tyrosine kinases in their search for oncogenic mutations, but the results of this study suggest that future searches should be much broader."