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Brain Tumors Evade Tailored Therapies by Eliminating Targeted Mutation

NEW YORK (GenomeWeb News) – Glioblastoma tumors essentially hide mutant EGFR in response to therapies targeting those mutations, a new study appearing in Science reported today. Further, after drug treatment is stopped, those mutations reappear.

"This discovery has considerable clinical implications because if cancer cells can evade therapy by a 'hide-and-seek' mechanism, then the current focus [of drug therapies] is unlikely to translate into better outcomes for patients," said
Paul Mischel from the Ludwig Institute for Cancer Research and the University of California, San Diego, School of Medicine in a statement.

In recent years there has been an emphasis on developing cancer therapies that are tailored to the mutations found in those tumors. Glioblastomas typically have mutant EGF receptors that drugs like erlotinib target.

"You would expect that drugs that block EGF receptor signaling would devastate GBM tumors," Mischel added. "Yet such targeted drugs have not worked in GBM, and that has raised some serious questions among cancer researchers."

More than 9,000 new GBM cases are diagnosed each year, according to UCSD, and the tumors are typically aggressive with a median patient survival rate of 14 months.

GBM tumors, though, are heterogeneous, and cells in the tumor express different levels of the EGFRvIII variant. That variant is constitutively active and is thought to stimulate tumor growth through various signaling mechanisms. This heterogeneity, the investigators suspected, could contribute to EGFR tyrosine kinase inhibitor resistance.

To test that idea, they performed single-cell analyses of samples from patient-derived xenograft GBM models that expressed EGFRvIII. Through quantitative microfluidic image cytometry, they found that some 60 percent of cells expressed detectable levels of EGFRvIII. Such EGFRvIIIHigh cells were also linked to increased tumor proliferation, decreased rate of basal apoptosis, and increased cell death in response to erlotinib treatment.

In mice with tumors, treatment with erlotinib at first led to an 80 percent shrinkage of the tumor. At the same time, the tumor shifted from containing mostly EGFRvIIIHigh cells to containing mostly EGFRvIIILow cells. The researchers noted that this effect was also seen in pre- and post-treatment samples from patients.

Additionally, both EGFRvIIIHigh cells and EGFRvIIILow cells appeared to be equally tumorigenic and gave rise to tumors with the same ratio of EGFRvIIIHigh cells to EGFRvIIILow cells as the original tumor. This, the researchers added, is consistent with a stochastic state transition model.

EGFRvIII arises due to an in-frame deletion of exon two through exon seven of the EGFR gene, and it is thought to be located on small, circular extrachromosomal bits of DNA called Double Minute chromosomes.

The investigators developed a reversible EGFR tyrosine kinase inhibitor resistance model and using FISH on treatment-naïve, resistant, and treatment-removed cells, they found high levels of EGFR extrachromosomal DNA in naïve and drug-removed samples, and low levels in the erlotinib-resistant samples.

They noted that the loss of EGFR extrachromosomal DNA in the treatment-resistant cells was specific as the cells still harbored other extrachromosomal elements. They confirmed this effect in patient-derived culture.

"This is, to the best of our knowledge, the first demonstration that reversible loss of an oncogene on extrachromosomal DNA can lead to targeted cancer drug resistance," Mischel said.

In patient-derived cultures, Mischel and his colleagues added, stopping erlotinib treatment for some 72 hours increased the number of EGFR DMs and led the cells to be sensitive again to the drug.

"Those DNA double minutes seem to hide out in a reservoir," said Mischel, "and when the drug is removed, the tumors come screaming back. When they return, the cells become susceptible once again to targeted therapy."

He also noted that these findings could influence the dosage of drugs administered to GBM patients.

"A high-dose regimen of EGF receptor-targeting drugs, given in pulses, might be more effective than the continuous, lower-dose regimen employed today," he added. "That is a study that needs to be done."

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