New lung cancer oncogene and target in NTRK1

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A subset of lung cancers are caused by mutations in the gene NTRK1, according to research presented at the annual meeting of the American Society of Clinical Oncology in early June in Chicago, Illinois.

“We're reconceptualizing lung cancer as many, related diseases. And we need to learn to identify and treat each individually. We can treat the forms of the disease that depend on ALK and EGFR mutations. We're getting very close to treating lung cancers that depend on ROS1 and RET. And now we show another oncogenic driver of the disease that begs its own targeted treatment,” said investigator Robert C. Doebele, MD, PhD, of the University of Colorado Cancer Center and CU School of Medicine in Aurora.

The research team, which collaborated with Dana-Farber Cancer Institute, started with lung cancer tumor samples from 36 “pan-negative” patients, meaning that no other driver oncogene had been identified. So, if it was not EGFR, ALK, and the like, then what was driving the cancer?

This research question was addressed through targeted, next-generation sequencing that analyzed the samples for possible mutations in a couple hundred potential oncogenes that are identified as drivers of other cancers. NTRK1 had been identified as a driver of thyroid cancer and so was included in the panel. However, drug development for NTRK1 had stalled, in part because of the relative rarity of the thyroid disease. The next-generation sequencing did identify NTRK1 gene fusions as the potential driver in two of these samples.

Next, a specific test for NTRK1 fusions was developed that is based on fluorescence in situ hybridization (FISH), similar to what is used for ALK, ROS1, and RET fusions. This allowed the group to validate the finding of NRTK1 as a novel oncogene in these patient samples.

Genes that are improperly activated can be silenced. Doebele said, “Many drugs exist to turn off these candidate genes, whether a drug is already is in clinical trials, or already approved for another cancer, or just sitting on the pharma shelf somewhere.”

In this case, Doebele described, “walking up the street to Array BioPharma (Boulder, Colorado), who happened to have several compounds specific for this gene.”

The researchers showed that mutated NRTK1 genes in cells treated with drug candidates ARRY-772, ARRY-523, ARRY-470, and others were effectively turned off.

“This is still preclinical work,” Doebele said, “but it's the first – and maybe even second and third! – important steps toward picking off another subset of lung cancer with a treatment targeted to the disease's specific genetic weaknesses.”
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