ALK, ROS1 and now NTRK1: Study shows prevalence of new genetic driver in lung cancer

May 31, 2014

A University of Colorado Cancer Center study presented at the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO) draws a line from mutation of the gene NTRK1, to its role as an oncogene in non-small cell lung cancer, to treatment that targets this mutation. The current study reports the prevalence of the NTRK1 mutation in an unselected population of 450 lung cancer samples, with >1% percent of patients testing positive. This and other work from Dr. Doebele's group forms the basis of a phase 1 clinical trial targeting NTRK1 mutations in advanced solid tumors (NCT02122913).

"Everything we know about points to the idea that when we find one of these genetic drivers and can target it with a drug, patients will respond and tend to have a good amount of time on drug before it becomes ineffective. Obviously we can't guarantee the effectiveness of targeting the NTRK1 mutation at this point, but everything we know about these kinds of genes makes us extremely hopeful," says Robert C. Doebele, MD, PhD, investigator at the CU Cancer Center and associate professor of Medical Oncology at the CU School of Medicine.

Previous work in collaboration with Pasi A. Jänne, MD, PhD from the Dana-Farber Cancer Institute, examined lung cancer tumor samples from 36 "pan-negative" patients, meaning that no other driver had been identified. Next-gen sequencing at Foundation Medicine (Cambridge, MA) identified NTRK1 gene fusions as the potential driver in two of these samples.

Doebele and colleagues took the finding back to 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 currently used for ALK, ROS1 and RET fusions. This test would allow rapid detection of NRTK1 oncogenes in patient samples.

"But no one had ever looked for NTRK1 mutations in a large series of unbiased patient samples," Doebele says. "The point of this study was to get a better sense of how many lung cancer patients are likely to be positive for NTRK1 mutations and what these patients are likely to look like."

Of 450 evaluated patient samples of non-small cell lung cancer, 5 tested "positive" and another 12 are considered suspicious for the mutation. Next generation sequencing studies revealed 5 previously undescribed NTRK1 mutations. Ongoing work seeks to tease apart the subtleties of diagnosis to further refine the criteria used to decide which tumors are truly created by the NTRK1 mutation.

Again, just as the FDA-approved drug crizotinib targets ALK fusions in an affected subset of lung cancer, the goal of the current line of research is to identify patients whose cancers are caused by NTRK1 and similarly target these patients with a drug that silences the problem gene. Toward that goal, Array BioPharma (Boulder, CO) provided candidate drugs to inhibit mutated NTRK1. Loxo Oncology, Inc. has managed further testing of the leading drug candidate, now known as LOXO-101. A phase 1a/1b clinical trial of the drug in advanced solid tumors is now recruiting .

"We found the mutation in a patient sample in 2012, published a manuscript in 2013 describing NTRK1 as a driver of lung cancer, and now here we are in May 2014 laying the groundwork for a clinical trial of drugs targeting this mutation," Doebele says. "Having seen this approach work well with other in the past, the team is optimistic that this research could help control another important subset of lung cancers."

Explore further: NTRK1: A new oncogene and target in lung cancer

Related Stories

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 ...

Study finds new genetic error in some lung cancers

October 28, 2013
A fine-grained scan of DNA in lung cancer cells has revealed a gene fusion – a forced merger of two normally separate genes – that spurs the cells to divide rapidly, scientists at Dana-Farber Cancer Institute and the ...

Responses with crizotinib in MET-amplified lung cancer show new targetable form of disease

May 31, 2014
A study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014 reports the results of a first-in-human, phase 1 dose escalation trial of crizotinib (XALKORI) in 14 patients with advanced, MET-amplified ...

Study finds known lung cancer oncogenes ALK and ROS1 also drive colorectal cancer

December 17, 2013
A University of Colorado Cancer Center study published online ahead of print in the journal Molecular Cancer Research shows that ALK and ROS1 gene rearrangements known to drive subsets of lung cancer are also present in some ...

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 ...

With early, obvious benefit of a targeted cancer drug, should expensive clinical testing continue?

August 8, 2013
Generally, FDA-approved clinical trials progress through three phases: the first shows safety, the second starts to explore effects and the third seeks to prove a drug's superiority over existing treatments. But when a drug's ...

Recommended for you

One to 10 mutations are needed to drive cancer, scientists find

October 19, 2017
For the first time, scientists have provided unbiased estimates of the number of mutations needed for cancers to develop, in a study of more than 7,500 tumours across 29 cancer types. Researchers from the Wellcome Trust Sanger ...

Gene circuit switches on inside cancer cells, triggers immune attack

October 19, 2017
Researchers at MIT have developed a synthetic gene circuit that triggers the body's immune system to attack cancers when it detects signs of the disease.

Researchers target undruggable cancers

October 19, 2017
A new approach to targeting key cancer-linked proteins, thought to be 'undruggable," has been discovered through an alliance between industry and academia.

Mutant gene found to fuel cancer-promoting effects of inflammation

October 19, 2017
A human gene called p53, which is commonly known as the "guardian of the genome," is widely known to combat the formation and progression of tumors. Yet, mutant forms of p53 have been linked to more cases of human cancer ...

New study reveals breast cancer cells recycle their own ammonia waste as fuel

October 19, 2017
Breast cancer cells recycle ammonia, a waste byproduct of cell metabolism, and use it as a source of nitrogen to fuel tumor growth, report scientists from Harvard Medical School in the journal Science.

Breast cancer researchers find bacteria imbalance link

October 19, 2017
Researchers in the United States have uncovered differences in the bacterial composition of breast tissue of healthy women versus those with breast cancer.

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.