Revisiting NTRKs as an emerging oncogene in hematological malignancies

Abstract

NTRK fusions are dominant oncogenic drivers found in rare solid tumors. These fusions have also been identified in more common cancers, such as lung and colorectal carcinomas, albeit at low frequencies. Patients harboring these fusions demonstrate significant clinical response to inhibitors such as entrectinib and larotrectinib. Although current trials have focused entirely on solid tumors, there is evidence supporting the use of these drugs for patients with leukemia. To assess the broader applicability for Trk inhibitors in hematological malignancies, this review describes the current state of knowledge about alterations in the NTRK family in these disorders. We present these findings in relation to the discovery and therapeutic targeting of BCR-ABL1 in chronic myeloid leukemia. The advent of deep sequencing technologies has shown that NTRK fusions and somatic mutations are present in a variety of hematologic malignancies. Efficacy of Trk inhibitors has been demonstrated in NTRK-fusion positive human leukemia cell lines and patient-derived xenograft studies, highlighting the potential clinical utility of these inhibitors for a subset of leukemia patients.

Fig. 1

This timeline highlights the discovery of NTRK-related alterations in a variety of hematologic malignancies in relation to milestone studies that ushered an era of precision oncology. The growing number of NTRK alterations found in hematologic malignancies over the years suggests that these alterations have profound clinical implications that warrant further investigation

Fig. 2

a Diagram of the unique Trk fusions identified in various hematological malignancies [52, 58, 66]. For each fusion, the carboxy-terminal kinase domain of the Trk protein is fused in-frame with the upstream amino-terminal binding partner. All relevant domains that contribute to the final chimeric fusion are shown. Vertical arrows indicate the breakpoint. PNT pointed domain, TM transmembrane domain. Fusions are numbered in the order they are discussed throughout the text. b Representative Trk receptor indicating location of known deletions [70] and point mutations [–79]