Scientists develop new strategy to overcome drug-resistant childhood cancer

A new drug combination could offer hope to children with neuroblastoma by boosting the effectiveness of a promising new gene-targeted treatment.

Dr Louis Chesler and colleagues found a way to overcome the resistance of cancer cells to a drug called crizotinib – which recently showed positive early results in its first trial in children with cancer – by combining it with a second class of drugs called mTOR inhibitors.

Crizotinib has already been licensed by the US Food and Drug Administration for use in adult cancers, but early experience suggests tumours eventually stop responding to treatment, after developing additional mutations in the ALK gene targeted by the drug.

The ICR scientists and colleagues at the Dana-Farber Cancer Institute and Children’s Hospital in Boston identified the strategy after revealing for the first time the role played by the ALK cancer-causing gene in driving neuroblastoma.

Neuroblastoma patients with ALK 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.

The team found that one point mutation to ALK, ALKF1174L, and changes in MYCN cause more aggressive, crizotinib-resistant neuroblastoma, by turning on the PI3K/AKT/mTOR pathway.

Combining an mTOR inhibitor with crizotinib prevented the growth of neuroblastoma by simultaneously inhibiting MYCN and ALK, overcoming the resistance of these tumours to treatment with crizotinib alone.

As well as delivering a strategy to overcome crizotinib resistance in general, this work highlights a treatment approach that may be effective for patients with aggressive neuroblastoma who carry both genetic changes at diagnosis.

The study was published in Cancer Cell.