The findings, which appear during the week of January 18 in an online early edition of the Proceedings of the National Academy of Sciences, provide both new insights into the behaviour of gliomas as well as potential new drug targets and treatment strategies.
"The results suggest that the expression of EGFR is required for tumours to keep growing, and we've shown for the first time that there are mechanisms that the tumour is using to circumvent the need for the receptor," said Frank Furnari, PhD, associate professor of medicine at the UCSD School of Medicine and associate investigator at the San Diego branch of the LICR, adding that other cancers may use similar tactics. "We need to find out more about the signaling pathways that brain tumours use to get around targeted therapeutics, such as those directed at EGFR."
In aggressive gliomas, extra copies of the EGFR gene are produced, and half of such tumours also carry an EGFR mutation, which ramps up tumour growth and portends a poor prognosis. Clinical trials of anti-EGFR agents have been disappointing; brain tumours may respond initially, but later become resistant to the drugs. To better understand why, Furnari, Webster Cavenee, PhD, professor of medicine and director of San Diego's LICR branch, and their group wanted to find out if the mutant EGFR was needed by tumours for their continued growth.
The team - including postdoctoral fellows Akitake Mukasa, MD, PhD, and Jill Wykosky, PhD - created a genetic system in mice in which they could control the expression of mutated EGFR, turning it off and on with the drug tetracycline. They found that the tumours' growth would stop for a period of time when tetracycline blocked EGFR, much like what is seen in patients who respond to EGFR inhibitors. But the tumours would start to grow again, even without EGFR, meaning something else was driving tumour growth.
The researchers examined individual tumours that had sidestepped or "escaped" the need for mutant EGFR to sustain their growth. In some cases, tumours that would normally have killed mice in 20 days were stable for months with the blocked expression of mutant EGFR. The scientists used microarray technology to test for genes that had not been previously expressed in the tumours but were now overexpressed in tumours that no longer required EGFR. They finally found one, KLHDC8 which, when inhibited, halted tumour growth.
"That finding makes us think that this gene would be a reasonable target," Cavenee said. "About half of the individual tumours that didn't need mutant EGFR to grow expressed that gene and, if we silenced the gene, those tumours did not grow."
Cavenee thinks this could be a model for the behaviour of other tumours. "If the tumours use the same strategy to get around receptor inhibitors, then targeting that alternate pathway plus the receptor up front should give a longer response because it's hitting the primary event plus the escape route," he said.
Now the research team is searching for other genes expressed in tumours that can escape EGFR dependence, and looking for biological pathways that might be involved.
