Posted: Sunday, August 1, 2021
For many adult and pediatric solid tumors, NTRK gene fusions, encoding TRK fusion proteins, are oncogenic drivers. Targeting these specific drivers with TRK inhibitors has become an effective treatment option for many patients with these genetic rearrangements. In a foundational review of these fusions and their clinical relevance, published in Nature Reviews Clinical Oncology, Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues explored the biology behind NTRK gene fusions, the efficacy of therapeutically targeting them, as well as strategies for managing both treatment-naive and acquired resistance to TRK inhibitors.
NTRK1 was first identified as an oncogene in 1982, followed by the discovery of TRKA in 1989, and the identification of family members TRKB and TRKC soon after that, the investigators stated. The TRK signaling pathway was observed to have a crucial role in neuronal differentiation and development. In very rare tumor types (eg, secretory breast cancer, mammary analog secretory carcinoma, cellular or mixed congenital mesoblastic nephroma, and infantile fibrosarcoma), these genetic alterations are also found at very high frequencies—often around 90%—but at lower frequencies in other cancers.
Various NTRK mutations and fusions have been identified as oncogenic drivers in a multitude of tumor types. The NTRK1 splice variant TRKAIII and the mutant delta-TRKA have both been detected in neuroblastoma and acute myeloid leukemia, respectively. Additionally, the overexpression of TRK has been observed in various cancers. Notably, overexpression of TRKA and TRKC was indicative of favorable outcomes, whereas TRKB was observed in high-grade tumors, according to Dr. Drilon and colleagues.
Latotrectinib remains the most specific TRK inhibitor used to treat patients with cancer, although entrectinib is also effective and inhibits ROS1 and ALK. Both pediatric and adult patients appeared to benefit from these agents in clinical trials, influencing their Breakthrough Therapy designation status from the U.S. Food and Drug Administration for the treatment of cancers with NTRK fusions. (Since this review was published, larotrectinib was approved in November 2018 and entrectinib in August 2019.)
Although some patients demonstrate resistance to TRK inhibition, it can be mediated by on- and off-target mechanisms such as NTRK kinase domain mutations. Second-generation TRK inhibitors such as selitrectinib (LOXO-195), repotrectinib (TPX-0005), and ONO-5390556 have been developed to combat resistance against latotrectinib and entrectinib and are currently being investigated.
Disclosure: For full disclosures of the study authors, visit nature.com.