NTRK1: A new oncogene and target in lung cancer

June 3, 2013

To the list of oncogenic drivers of lung cancer that includes ALK, EGFR, ROS1 and RET, results of a University of Colorado Cancer Center study presented at ASCO 2013 show that mutations in the gene NTRK1 cause a subset of lung cancers.

"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," says Robert C. Doebele, MD, PhD, investigator at the CU Cancer Center and assistant professor of at the CU School of Medicine.

The group, in collaboration with Pasi A. Jänne, MD, PhD from the Dana-Farber Cancer Institute, started with lung cancer tumor samples from 36 "pan-negative" patients, meaning that no other driver had been identified. So if not EGFR, ALK and the like, what was driving the cancer? Doebele and colleagues took the question to Foundation Medicine (Cambridge, MA), which used targeted, next-gen sequencing to analyze the samples for possible mutations in a couple hundred potential oncogenes identified as drivers of other cancers. NTRK1 had been identified as a driver of and so was included in the panel (though drug development had stalled due in part to the relative rarity of the ). Sure enough, next-gen sequencing identified NTRK1 gene fusions as the potential driver in two of these samples.

Doebele and colleagues took the lead back to the CU labs, where Marileila Varella Garcia, PhD, developed a specific test for NTRK1 fusions 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.

But the study went a step beyond identifying the oncogene. Doebele describes the relative ease with which genes that are improperly activated can be silenced – "whether a drug is already is in clinical trials, or already approved for another cancer, or just sitting on the pharma shelf somewhere, many drugs exist that turn off these candidate genes," Doebele says.

In this case, Doebele describes "walking up the street to Array BioPharma (Boulder, CO), who happened to have several compounds specific for this gene."

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

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

Explore further: RET rearrangement a new oncogene and potential target in lung cancer

Related Stories

RET rearrangement a new oncogene and potential target in lung cancer

June 3, 2013
In results presented at ASCO 2013, a University of Colorado Cancer Center study provides important details for a recently identified driver and target in lung adenocarcinoma: rearrangement of the gene RET. The finding is ...

New research confirms need for lung cancer testing

February 2, 2012
Different kinds of lung cancer behave in different ways, suggesting they are fundamentally different diseases. According to a University of Colorado Cancer Center study published in Cancer, the official journal of the American ...

Targeted therapy boosts lung cancer outcomes

June 1, 2013
–Thousands of patients with an advanced form of lung cancer that carries a specific dysfunctional gene are likely to fare better if treated with a targeted therapy than with traditional chemotherapy, report Dana-Farber ...

Tumors with ALK rearrangements can harbor more mutations

April 22, 2013
The identification of potentially targetable kinase mutations has been an exciting advancement in lung cancer treatment. Although the mutations driving many lung carcinomas remain unknown, approximately 50 percent of lung ...

Study examines drug resistance in ALK positive lung cancer

January 19, 2012
Scientists from the University of Colorado Cancer Center have once again advanced the treatment of a specific kind of lung cancer. The team has documented how anaplastic lymphoma kinase (ALK) positive advanced non-small cell ...

Not all lung cancer patients who could benefit from crizotinib are identified by FDA-approved test

August 28, 2012
Break apart a couple worm-like chromosomes and they may reconnect with mismatched tips and tails – such is the case of the EML4-ALK fusion gene that creates 2-7 percent of lung cancers. Almost exactly a year ago, the FDA ...

Recommended for you

Study suggests colon cancer cells carry bacteria with them when they metastasize

November 24, 2017
(Medical Xpress)—A team of researchers working at Harvard University has found evidence that suggests a certain type of bacteria found in colon cancer tumors makes its way to tumors in other body parts by traveling with ...

Promising new treatment for rare pregnancy cancer leads to remission in patients

November 24, 2017
An immunotherapy drug can be used to cure women of a rare type of cancer arising from pregnancy when existing treatments have failed.

Researchers unravel novel mechanism by which tumors grow resistant to radiotherapy

November 23, 2017
A Ludwig Cancer Research study has uncovered a key mechanism by which tumors develop resistance to radiation therapy and shown how such resistance might be overcome with drugs that are currently under development. The discovery ...

African Americans face highest risk for multiple myeloma yet underrepresented in research

November 23, 2017
Though African-American men are three times more likely to be diagnosed with multiple myeloma, a type of blood cancer, most scientific research on the disease has been based on people of European descent, according to a study ...

Encouraging oxygen's assault on iron may offer new way to kill lung cancer cells

November 22, 2017
Blocking the action of a key protein frees oxygen to damage iron-dependent proteins in lung and breast cancer cells, slowing their growth and making them easier to kill. This is the implication of a study led by researchers ...

One-size treatment for blood cancer probably doesn't fit all, researchers say

November 22, 2017
Though African-American men are three times more likely to be diagnosed with a blood cancer called multiple myeloma, most scientific research on the disease has been based on people of European descent, according to a study ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.