EGFR Signaling Could be Harnessed to Fight Cancer

Many new cancer drugs target the epidermal growth factor receptor (EGFR) protein, which plays a role in cellular processes and proliferation of cancer cells. In a new study published by Cell, investigators made a significant discovery about EGFR signaling that may lead to novel cancer drugs.

It is known that part of the EGRF protein is on the inside of the cell and also has another part on the outside of the cell, according to the study authors.

“When signaling molecules known as growth factors bind to the outside part of EGFR, they trigger the enzyme within the inside part, and initiate proliferation or other cellular responses,” said corresponding author Mark Lemmon, PhD, FRS.

Current treatments that target EGFR—including those for breast cancer—shut off the receptor to prevent cancer growth.

“Researchers have long known that growth factors activate EGFR by ‘stitching’ 2 receptor molecules together,” Dr Lemmon said. “This paradigm has always suggested that the receptor has to be either ‘off’ or ‘on’, so all EGFR drugs have been designed to shut off the receptor and thus shut off proliferation.”

However, there have been gaps in knowledge about EGFR. Although the protein is regulated by 7 growth factors that can make the cell carry out different actions, it has been unknown how the different actions can be driven by a single binding scenario, according to the study.

The authors conducted X-ray crystallography to better understand EGFR, which included crystalizing the outside part of the protein, shining x-rays on the crystals, collecting data on how the rays diffract, and building its structure.

After deriving the structure of EGFR from the data, the authors explored the relationship with biological mechanisms seen in cellular experiments, according to the study.

The authors noted that EGFR signaling is not an on/off process that occurs when the receptors are stitched together. They discovered that growth factors can turn on the receptor in multiple ways, depending on the strength of the stitch and timing, according to the study.

“We can imagine that instead of therapeutics that just shut off EGFR, we might design new ones that encourage it to give a beneficial signal,” Dr Lemmon said.

The study showed that growth factors that stitch the receptors together weakly for a short period of time transform the cell into another cell type and does not cause it to proliferate. The investigators speculate that a drug that causes this may prevent cancer cells from proliferating.

The various effects from EGFR binding may also increase the understanding of liver cancer, which are driven by similar mechanisms that are currently unknown, according to the study.

“There are cancer drugs against EGFR that really work, but we need new ways to develop them, because cancers can develop resistance to all of them,” Dr Lemmon concluded.