Loss of Antitumor Protein Could Explain Why EGFR Therapy Resistance Occurs

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This is a structure showing EGFR—a cancer driver—in its active dimer conformation. Red indicates mutations that destroy the protein-protein interface. [Eduard Porta Pardo]
This is a structure showing EGFR—a cancer driver—in its active dimer conformation. Red indicates mutations that destroy the protein-protein interface. [Eduard Porta Pardo]

Low levels of a protein called p120 catenin, thought to help prevent tumor formation, may explain why some patients develop resistance to EGFR targeted cancer therapy.

In an early-stage study carried out using cancer cell lines, researchers based at the Penn State University College of Medicine showed that cells with high EGFR levels alone were responsive to therapy, but those with high EGFR levels and low p120 catenin levels soon developed resistance.

The epidermal growth factor receptor gene EGFR encodes a transmembrane protein that has an important role in cell division and survival. Mutations in EGFR can result in overexpression of the protein and uncontrolled cell division and this is linked with many different cancers including lung adenocarcinoma, anal cancers and glioblastoma, among others. High EGFR levels tend to be linked to a poor cancer prognosis.

The first drug developed to target abnormal EGFR expression was gefitinib, which was approved in 2003. Since then, at least four more drugs in this class have been approved such as erlotinib and afatinib. Although EGFR targeting therapies are effective in 75% of patients, many develop resistance and relapse within the first year of treatment.

Reasons for around 70% of relapses are known. These can be due to EGFR mutations, or blocking of cell pathways needed for the protein to function properly among other things. However, around 30% of cases are unaccounted for.

“There are still some reasons for resistance that are alluding scientists,” said Stairs, a Penn State Cancer Institute researcher. The team’s previous work showed that too much EGFR and low p120 catenin can cause cancer to develop. “We hypothesized that reduced amounts of p120 catenin might also cause resistance to EGFR therapies.”

As described in the journal PLoS ONE, Stairs and team cultured genetically-engineered esophageal cancer cells before treating them with the EGFR targeted drug gefitinib. One cell line had normal levels of both EGFR and p120 catenin, one had high EGFR, one high p120 catenin, and one high EGFR and low p120 catenin.

Of the two groups of cells with high EGFR, those with normal levels of p120 catenin died as if the therapy was working. But, the cells in the group with high EGFR and low p120 catenin resisted treatment with gefitinib.

These results are promising, but still at an early stage. The researchers plan to look at cells from patients with EGFR positive cancers that are resistant to therapies to study the action of p120 catenin further. They also plan to confirm whether this resistance occurs across all drugs targeting EGFR cancers.

“We also need to investigate further how the loss of p120 catenin causes this resistance,” Stairs said. “For now, we know that if patients who have high levels of EGFR in their samples were also tested for their levels of p120 catenin, it may provide a clue to clinicians as to which patients are at risk for resistance to EGFR-targeting therapies or relapse.”

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