Are NTRK Fusions ‘Bona Fide’ Oncogenic Drivers of Lung Cancer?
Posted: Thursday, December 23, 2021
A review article published in Lung Cancer by a group of researchers affiliated with New York’s Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center described the prevalence and role of NTRK fusions in non–small cell lung cancer (NSCLC). Alexander Drilon, MD, and colleagues offer a closer look into the biomechanics behind these gene fusions as well as the diagnostic and treatment options clinicians may elect to use in NTRK fusion–positive cancers.
NTRK fusions are formed by chromosomal rearrangements in which 3’ sequences of NTRK1, NTRK2, or NTRK3 are joined to 5’ sequences of other genes. This leads to constitutive ligand–independent kinase activity and increased TRK kinase expression. Fusions are much more common among rare cancers—such as congenital fibrosarcoma and subtypes of congenital mesoblastic nephroma—than they are among common cancers like non-secretory breast or lung cancer. NTRK fusions appear in more than 90% of these rare cancers, making them almost characteristic of these disease types. However, in NSCLC, the prevalence of these fusions is estimated to be between 0.1% and 0.3%.
The preferred method of NTRK fusion testing includes a combination of hybrid capture DNA- and RNA-based next-generation sequencing. Two clinically approved treatments are first-generation TRK inhibitors larotrectinib and entrectinib, which have become the standard in treating NTRK fusion–positive cancers. Both act in the way of decreasing ATP binding to TRK proteins and can cross the blood-brain barrier—demonstrating efficacy in treating brain metastases as well as primary central nervous system tumors. As for adverse effects, among the most common with these agents are dizziness, weight gain, paresthesia, and withdrawal pain.
An issue with these treatments, however, is resistance—which arises from NTRK kinase domain mutations. Next-generation TRK inhibitors including selitrectinib and repotrectinib can engage the ATP pocket without steric hinderance from TRK substitutions, which makes them helpful in combating resistance. Both are currently in early-phase clinical trials.
Disclosure: For full disclosures of the study authors, visit sciencedirect.com.