Revisiting Ntrks As an Emerging Oncogene in Hematological Malignancies
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Leukemia (2019) 33:2563–2574 https://doi.org/10.1038/s41375-019-0576-8 REVIEW ARTICLE Molecular targets for therapy Revisiting NTRKs as an emerging oncogene in hematological malignancies 1,2,3 4,5 1,3,6 1,3,6 Sunil K. Joshi ● Monika A. Davare ● Brian J. Druker ● Cristina E. Tognon Received: 11 June 2019 / Accepted: 18 June 2019 / Published online: 24 September 2019 © The Author(s) 2019. This article is published with open access 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 fi 1234567890();,: 1234567890();,: that NTRK fusions and somatic mutations are present in a variety of hematologic malignancies. Ef cacy 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. Introduction understanding of the biology contributing to malignant phenotypes. A seminal example is the identification of the Advances in technologies from chromosomal banding to BCR–ABL1 fusion protein in chronic myeloid leukemia massively parallel sequencing have enabled the identifica- (CML) [1–4]. Studies of BCR–ABL1 have not only shaped tion of oncogenic mutations, and enhanced our our understanding of the tumorigenic process but also provided insight into how cancer can be treated. The dis- covery and success of imatinib, the first FDA-approved tyrosine kinase inhibitor against BCR–ABL1, has revolu- * Brian J. Druker tionized how we approach the treatment of cancer [5, 6]. [email protected] Importantly, this paved the way for precision oncology, * Cristina E. Tognon wherein development of selective, molecularly-guided [email protected] therapeutic modalities have shown significant improve- ments in patient outcomes, as compared with nonselective 1 Knight Cancer Institute, Oregon Health & Science University, chemotherapeutics. This principle has also been shown to Portland, OR, United States be effective in the treatment of several solid and liquid 2 Department of Physiology & Pharmacology, School of Medicine, tumors [7–9], underscoring the broad value of using drugs Oregon Health & Science University, Portland, OR, United States that precisely target cancer driving lesions. 3 Division of Hematology & Medical Oncology, Department of Recently, the FDA granted accelerated approval to lar- Medicine, Oregon Health & Science University, Portland, OR, United States otrectinib (also commonly referred to as LOXO-101 or Vitrakvi™), the first selective neurotrophic tyrosine receptor 4 Papé Pediatric Research Institute, Oregon Health & Science University, Portland, OR, United States kinase (NTRK) inhibitor for patients of all ages with 5 advanced solid tumors harboring NTRK gene fusions, Division of Pediatric Hematology & Oncology, Department of fi Pediatrics, Oregon Health & Science University, Portland, OR, regardless of tumor histology [10, 11]. The ef cacy and United States safety profile of larotrectinib were confirmed in three 6 Howard Hughes Medical Institute, Oregon Health & Science independent trials with patients ranging from all ages (the University, Portland, OR, United States youngest being a 1-month-old) [11–13]. Interestingly, 2564 S. K. Joshi et al. NTRK gene fusions occur at higher frequency (up to 90%) molecular events such as chromosomal rearrangements, in patients with rare cancers, such as infantile fibrosarcoma, deletions/truncations, point mutations, and changes in secretory breast carcinoma, mammary analogue secretory mRNA and protein expression. Among these mechanisms, carcinoma, and cellular or mixed congenital mesoblastic oncofusions involving NTRK receptors are the most com- nephroma, but are less prevalent in common adult tumors mon mechanism of activation. [14]. With an overall response rate of >75%, a median duration of response not reached following 18 months, and NTRK oncofusions minimal adverse effects, larotrectinib’sefficacy parallels that of imatinib, and marks another milestone for the field of In 1986, shortly after the confirmation of BCR–ABL1 in precision oncology [12]. Even more recently, entrectinib, a CML [2], the first gene fusion involving an NTRK receptor pan-Trk, ROS1, and ALK inhibitor also received acceler- was identified in a patient with colorectal cancer (Fig. 1). ated FDA approval [15]. Similar to imatinib, the approval This oncogenic translocation, TPM3-TRK, resulted from of larotrectinib and entrectinib remind us of the importance the fusion of the tropomyosin 3 gene amino terminus with of understanding the biological target as a stringently vetted the transmembrane and kinase domains of NTRK1 [19], a response biomarker, and the need to continue screening for finding that has since been confirmed [36]. Over the past other actionable targets by harnessing the rapidly amassing few years, several NTRK fusions have been reported in ‘omics data. solid tumors [34, 35, 37, 38]. Moreover, with the approval of larotrectinib and Many of these Trk fusions involve the transcription entrectinib, the Trk family of cell surface tyrosine kinase factor, E26 transformation-specific variant 6 (ETV6, also receptors have drawn considerable attention. NTRK1, 2, known as TEL) located on chromosome 12p13. Specifi- and 3 genes encode TrkA, TrkB, and TrkC receptors, cally, ETV6–NTRK3 fusions (EN; t(12;15) (p13;q25)) have respectively. These receptors signal through JAK/STAT, been previously characterized in the setting of secretory PI3K/AKT, and MEK/ERK to promote proliferation, dif- breast carcinoma [24, 39], congenital fibrosarcoma [40], ferentiation, and survival [16, 17]. Although much of the thyroid carcinoma [41], and pontine gliomas [23]. Inter- literature has focused on the importance of these receptors estingly, the EN fusion is the first oncogenic fusion to be in central and peripheral nervous system development and identified in cancers that are derived from all three cell function [18], alterations in the NTRK family have been lineages [35]. In the most common version of the EN described in colon [19], thyroid [20, 21], lung [22], glial fusion, the amino terminus of the ETV6 transcription factor, [23], and breast [24] cancers. These alterations are found at containing the helix-loop-helix (HLH) domain (exons 1–5; relatively low frequencies (<1%) within each of these also commonly referred to as the sterile alpha motif or individual solid tumors but collectively, when considering pointed domain), fuses with the kinase domain of the all tissues, NTRK-driven cancers constitute a significant partnering protein resulting in constitutive kinase activity number of patients, making them an important therapeutic [42, 43]. The ETV6 HLH domain has been shown to be target [22, 25–28]. Notably, NTRK fusions are pathogno- essential for mediating protein activity of the EN fusion. Its monic for several rare solid tumor malignancies deletion results in the loss of dimer formation and ability to [24, 26, 29–33]. A number of excellent reviews have transform mutant cells [44]. Substituting the ETV6 HLH summarized recent work on Trk signaling in solid tumors domain with an inducible FK506 binding protein dimer- [14, 16, 34, 35]. Despite the emerging success of NTRK ization domain does not inhibit catalytic activation of the inhibition in solid tumors, the role of these receptors in fusion, but abrogates its transformative capacity. These data hematologic malignancies remains under investigated. suggested that the ETV6 HLH domain provides specific Therefore, this review provides a comprehensive overview signaling or polymerization capabilities required for full of our current understanding of NTRK-mediated tumor- activation of the fusion protein [45–47]. igenesis in hematological malignancies and links recent Although other, non-NTRK ETV6-based fusions have successes in NTRK-targeted therapy to historical milestones been long reported to play a role in leukemogenesis achieved by the targeting of BCR–ABL1 in CML. [42, 48–51], an EN fusion was first reported in 1999 by Eguchi et al. [52, 53] in a 59-year-old female with AML- M2 using fluorescence in situ hybridization (FISH). They NTRK receptor alterations and their role in identified two variants of the fusion with FISH (Fig. 2a). In cancer development each case, exons 1–4 of the ETV6 HLH domain were fused in-frame with exons 13–18 of NTRK3 that encoded the To date the BCR–ABL1 fusion remains the most prevalent protein-tyrosine kinase (PTK) domain. These fusions dif- mechanism of oncogenic ABL activation. In contrast acti- fered from the EN fusions described in solid tumors as only vation of NTRK receptors can result from a wider range of the first four exons of ETV6 were fused with the kinase Revisiting NTRKs as an emerging oncogene in hematological malignancies 2565