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Strategy Proposed for Overcoming Resistance to Cancer Drug

Louis Chesler (Courtesy, Sparks)

Louis Chesler (Courtesy, Sparks)

Researchers in the U.K., with colleagues from the U.S. and Sweden, have recommended a way to overcome the resistance of cancer cells to the drug crizotinib, which recently showed positive results in its first trial in children with cancer. The findings are published online this week in the journal Cancer Cell (paid subscription required).

Louis Chesler, who heads the Neuroblastoma Drug Development Team at the Institute of Cancer Research (ICR) in London, led the research team with participants from ICR, Dana-Farber Cancer Institute and Children’s Hospital in Boston, Memorial Sloan-Kettering Cancer Center in New York, and Umeå University in Sweden. Chesler’s team focused on resistance that develops to the drug crizotinib, marketed as Xalkori by Pfizer, which has been approved by the FDA to treat some adult cancers and has shown promise in early trials for children with cancer.

Experience with crizotinib to date indicates tumors stop responding to treatment by the drug after developing additional mutations in the anaplastic lymphoma kinase (ALK) gene targeted by the drug. The ALK cancer-causing gene plays a role as a driver of neuroblastoma, a cancer of the nervous system that affects about 1 out of 100,000 children, and which accounts for about 15 percent of children’s cancer deaths in the U.K.

Neuroblastoma patients with ALK gene mutations frequently have alterations to the MYCN gene, which is closely linked to the development of aggressive neuroblastoma, but is difficult to target directly with drugs. Faced with this set of conditions, Chesler and colleagues investigated how a common ALK mutation and alterations in MYCN interact to drive the onset of neuroblastoma, and to find a way to overcome resistance to crizotinib.

They found the interaction of the mutant ALK and altered MYCN genes turned on a pathway for a third type of gene, mTOR. The researchers say the pathway has been linked to the development of neuroblastoma and many adult cancer types, and has been a focus of drug-development in adult cancer.

Chesler’s team tested in mice an mTOR inhibitor called torin2 in combination with crizotinib. They found combining the mTOR inhibitor with crizotinib prevented the growth of neuroblastoma by simultaneously inhibiting MYCN and ALK, thus overcoming the resistance of these tumors to treatment with crizotinib alone.

“We hope that our work will benefit children with neuroblastoma by increasing the effectiveness of crizotinib,” says Chesler. “Our study may also have relevance for adult patients with ALK-driven lung cancer and lymphoma who develop resistance to crizotinib….”

The study was funded by a number of philanthropies, including The Neuroblastoma Society, Cancer Research UK, Sparks — the children’s medical research charity, and The Rooney Foundation.

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