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Dec 6, 2013

Cancer Plays Rope-a-Dope to Resist Targeted Therapy

  • Cancer is known to stubbornly resist targeted therapies, but exactly how remains unclear. Cancer, some scientists believe, plays tricks with extrachromosomal DNA, using it, for the most part, to encode multiple copies of proteins that detoxify chemotherapy or drive cancer in other ways, such as the generation of alternative signaling molecules. Such mechanisms suggest that cancer evades targeted therapy by setting up a game of whack-a-mole. But cancer, it now appears, may resort to another strategy—rope-a-dope.

    Like a boxer huddled against the ropes, absorbing an opponent’s punches, tumor cells may temporarily go on the defensive, ceasing their expression of the very signaling molecules that make them vulnerable to targeted therapies. Whereas the boxer comes out swinging after exhausting his opponent, tumor cells may resume proliferating after therapy is removed.

    The details of how cancer manages this trick are presented in a paper published December 5 in Science, in an article entitled, “Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA.” This paper describes how glioblastoma (GBM), the most common kind of brain cancer, evades targeted therapies by essentially hiding a signaling molecule, EGFRvIII, a mutant form of the EFG receptor. Without this receptor, tumor cells are able to resist EGFR tyrosine kinase inhibitors (TKIs).

    The gene for EGFRvIII lies on small fragments of DNA known as double minute chromosomes and promotes uncontrolled cell proliferation. According to Paul Mischel, M.D., an author of the paper and a scientist at the Ludwig Institute for Cancer Research, University of California at San Diego, “You would expect that drugs that block EGF receptor signaling would devastate GBM tumors. Yet such targeted drugs have not worked in GBM.”

    Only about 60% of cells express the aberrant receptor. To probe how this heterogeneity contributes to drug resistance, Dr. Mischel and his colleagues treated tumors taken from patients with targeted therapies. They found, to their surprise, that this prompted GBM cells to almost completely shut down their expression of EGFRvIII.

    The scientists followed up with single-cell analyses of patient-derived models and clinical samples from GBM patients treated with TKIs to demonstrate that tumor cells “reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth.” The scientists also determined that resistance to EGFR TKIs occurs by elimination of mutant EGFR from extrachromosomal DNA.

    These findings show that GBM tumors don’t survive targeted therapy by replacing susceptible cells with mutants unaffected by the drugs in question—a classical mechanism of resistance—but by hiding the target of those drugs. And they did this, surprisingly, by depleting the double minute chromosomes themselves. “Those DNA double minutes seem to hide out in a reservoir,” said Dr. Mischel, “and when the drug is removed, the tumors come screaming back. When they return, the cells become susceptible once again to targeted therapy.”

    “Our research might have significant implications for how we dose patients,” said Dr. Mischel. “A high-dose regimen of EGF receptor-targeting drugs, given in pulses, might be more effective than the continuous, lower-dose regimen employed today. That is a study that needs to be done.”



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