TRK Cancer-Causing Mutation Discovered in 1982 Finally Target of Clinical Trials

Matching drugs to long-overlooked oncogene

In 1982, the gene TRK was shown to cause a small percentage of colon cancers. In 2013 and 2014, next-generation sequencing of tumour samples found fusions of the TRK family of genes in different tumour types, including lung, breast, melanoma and more. An article in the journal Cancer Discovery describes clinical trials at the University of Colorado Cancer Center and elsewhere that match drugs to this long-overlooked oncogene, offering targeted treatment opportunity for cancers that harbor these gene abnormalities (e.g. #NCT02122913).

Precision oncology approaches have accelerated recently due to advancements in ability to detect oncogenic mutations in tumour samples. Oncogenic alterations, most commonly gene fusions, have now been detected for the genes encoding the TRKA, TRKB, and TRKC receptor tyrosine kinases across multiple tumour types. The scientific rationale for the targeting of the TRK oncogene family is discussed in the paper, along with TRK family of receptors, their role in human cancer, the types of oncogenic alterations, and drugs that are currently in development for this family of oncogene targets.

The use of high-throughput next-generation sequencing techniques has identified NTRK1, 2, and 3 gene rearrangements encoding novel oncogenic fusions in 19 different tumour types to date. These recent developments have led to revisit an old oncogene, Trk (originally identified as OncD), which encodes the TPM3–NTRK1 gene fusion and was one of the first transforming chromosomal rearrangements identified. However, no drug has yet been approved by the FDA for cancers harbouring this oncogene.

The TRK family of genes is important in the developing nervous system. In the uterus, these genes and the proteins they encode are essential for the growth and survival of new neurons. After birth, these genes are unneeded in many tissues and so are programmed to go dormant. Some cancers wake them up - when improperly fused with other nearby genes, genes in the TRK family can restart their ability to signal cells to grow and become immortal, which in adult tissues can cause cancer.

"What we're finding is that while TRK fusions may not be the major cause in any single, major cancer, it's the cause of small percentages of many cancer types," says Dr Robert Doebele, investigator at the University of Colorado Cancer Center and associate professor of Medical Oncology at the University of Colorado School of Medicine.

The article cites studies showing NTRK fusions in 3.3% of lung cancers, 1.5% of colorectal cancers, 12.3% of thyroid cancers, about 2% of glioblastomas, and 7.1% of paediatric gliomas.

A decade ago, the NTRK fusion and other, related gene rearrangements were un-druggable. Now, an entire class of drugs has been developed to target this type of genetic abnormality. A host of new drugs in the class of tyrosine kinase inhibitors target TRK fusions, for example investigational anti-cancer agents RXDX-101, TSR-011, LOXO-101, PLX-7486 and more.

"A lot of doctors in academia or community hospitals are ordering next-generation sequencing panels for their patients. If it turns out that patients' tumors have TRK alterations, I want their doctors to know that there are treatment options available via clinical trials," Dr Doebele says.

Vaishnavi A, Le AT, Doebele RC.  TRKing Down an Old Oncogene in a New Era of Targeted Therapy. Cancer Discovery 2014; Published Online First December 19; doi: 10.1158/2159-8290.CD-14-0765