Abstract
Unlike many conventional cancers with preferential patterns of oncogenic genetic alterations, TRK fusions resulting from NTRK1/2/3 genetic alterations drive oncogenic transformations in more than 20 different malignancies over diverse tissue/cell lineages, in both children and adults. A recent “basket” study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly. Here, we discuss the larotrectinib study and perspectives and challenges in developing “tumor-agnostic” targeted therapies in rare tumors.
Highlights
Cancers are classified and treated based on their pathologic classification and tissue of origin
The BRAFV600 mutation occurs at high frequencies in specific tumor types, e.g., melanoma, thyroid cancer, hairy cell leukemia, Langerhans cell histiocytosis, and colorectal cancer, and at significantly lower frequencies in other tissue lineages
TRK fusions are rare but drive oncogenesis in diverse tissue lineages The NTRK1, NTRK2, and NTRK3 genes, encoding the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC, respectively, are receptor tyrosine kinases that are normally expressed in the nervous system [4]
Summary
Cancers are classified and treated based on their pathologic classification and tissue of origin. The BRAFV600 mutation occurs at high frequencies in specific tumor types, e.g., melanoma, thyroid cancer, hairy cell leukemia, Langerhans cell histiocytosis, and colorectal cancer, and at significantly lower frequencies in other tissue lineages. TRK fusions are rare but drive oncogenesis in diverse tissue lineages The NTRK1, NTRK2, and NTRK3 genes, encoding the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC, respectively, are receptor tyrosine kinases that are normally expressed in the nervous system [4]. With the exception of several rare tumor types (e.g., secretory breast carcinoma, mammary analog secretory carcinoma, congenital fibrosarcomas, and congenital mesoblastic nephroma), the majority of the TRK fusions occur in low frequencies in a variety of common cancers over a diverse tissue/cell lineages (e.g., lung adenocarcinoma, sarcoma, acute myeloid leukemia, colorectal cancer) [6, 7] (Table 1). Because of large introns, these fusions are difficult to detect using multiplex targeted exome capture panels (e.g., FoundationOne®, MSK-IMPACTTM)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
