Skip to main content
SpringerLink
Log in

The Evolving Diagnostic and Treatment Landscape of NTRK-Fusion-Driven Pediatric Cancers

  • Review Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

The neurotrophin receptor tyrosine kinase (NTRK1-3) genes have been identified as key fusion partners in a range of pediatric cancers. In childhood cancers, ETV6-NTRK3 fusions are found in the majority of infantile fibrosarcomas and congenital mesoblastic nephromas. NTRK fusions are also found in mammary analog secretory carcinomas (MASC), secretory breast carcinomas, and with modest frequency in high-grade gliomas in very young children. While there are a range of multi-receptor tyrosine kinase inhibitors that show efficacy against TRK kinases, there are now multiple highly selective TRK inhibitors in clinical evaluation. Entrectinib and larotrectinib have been evaluated in early-phase clinical trials for children and demonstrated high response rates with good durability of response. Both agents are now approved in the United States in an age and histology agnostic manner for children (age > 12 years for entrectinib; all ages for larotrectinib) for the treatment of solid tumors harboring NTRK fusions without an option for complete surgical resection, with relapsed disease, or without a viable alternative systemic option. More recently, two second-generation TRK inhibitors, selitrectinib and repotrectinib, have been developed and are currently being evaluated in pediatric early phase trials. The Children’s Oncology Group has also launched a phase II trial of larotrectinib as a neoadjuvant agent for patients with newly diagnosed infantile fibrosarcoma. While the clinical use of these agents has developed rapidly, many questions remain in terms of duration of therapy, treatment of CNS disease, and long-term toxicities. Further development of this class of agents will continue to require multi-center trials for these rare tumors. Tumor sequencing and potentially sequencing of circulating tumor DNA will improve our understanding of patterns of resistance and the most effective treatment strategies for these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M. Oncogenes in solid human tumours. Nature. 1982;300(5892):539–42.

    CAS  PubMed  Google Scholar 

  2. Klein R, Parada LF, Coulier F, Barbacid M. trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. EMBO J. 1989;8(12):3701–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lamballe F, Klein R, Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991;66(5):967–79.

    CAS  PubMed  Google Scholar 

  4. Kaplan DR, Hempstead BL, Martin-Zanca D, Chao MV, Parada LF. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science. 1991;252(5005):554–8.

    CAS  PubMed  Google Scholar 

  5. Davies AM, Horton A, Burton LE, Schmelzer C, Vandlen R, Rosenthal A. Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. J Neurosci. 1993;13(11):4961–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J, et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell. 1991;65(5):895–903.

    CAS  PubMed  Google Scholar 

  7. Cunningham ME, Greene LA. A function-structure model for NGF-activated TRK. EMBO J. 1998;17(24):7282–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1545–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 2003;72(1):609–42.

    CAS  PubMed  Google Scholar 

  10. Barbacid M, Lamballe F, Pulido D, Klein R. The trk family of tyrosine protein kinase receptors. Biochim Biophys Acta. 1991;1072(2–3):115–27.

    CAS  PubMed  Google Scholar 

  11. Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001;169(2):107–14.

    CAS  PubMed  Google Scholar 

  12. Minichiello L, Casagranda F, Tatche RS, Stucky CL, Postigo A, Lewin GR, et al. Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. Neuron. 1998;21(2):335–45.

    CAS  PubMed  Google Scholar 

  13. Postigo A, Calella AM, Fritzsch B, Knipper M, Katz D, Eilers A, et al. Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons. Genes Dev. 2002;16(5):633–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Klein R, Smeyne RJ, Wurst W, Long LK, Auerbach BA, Joyner AL, et al. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell. 1993;75(1):113–22.

    CAS  PubMed  Google Scholar 

  15. Huehne K, Zweier C, Raab K, Odent S, Bonnaure-Mallet M, Sixou J-L, et al. Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. Neuromuscul Disord. 2008;18(2):159–66.

    PubMed  Google Scholar 

  16. Schulte JH, Schramm A, Klein-Hitpass L, Klenk M, Wessels H, Hauffa BP, et al. Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas. Oncogene. 2005;24(1):165–77.

    CAS  PubMed  Google Scholar 

  17. Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer R, Varela CR, et al. Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res. 2009;15(10):3244–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol. 1994;14(1):759–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Evans AE, Kisselbach KD, Yamashiro DJ, Ikegaki N, Camoratto AM, Dionne CA, et al. Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts. Clin Cancer Res. 1999;5(11):3594–602.

    CAS  PubMed  Google Scholar 

  20. Thress K, Macintyre T, Wang H, Whitston D, Liu Z-Y, Hoffmann E, et al. Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway. Mol Cancer Ther. 2009;8(7):1818–27.

    CAS  PubMed  Google Scholar 

  21. Zage PE, Graham TC, Zeng L, Fang W, Pien C, Thress K, et al. The selective Trk inhibitor AZ623 inhibits brain-derived neurotrophic factor-mediated neuroblastoma cell proliferation and signaling and is synergistic with topotecan. Cancer. 2011;117(6):1321–91.

    CAS  PubMed  Google Scholar 

  22. Croucher JL, Iyer R, Li N, Molteni V, Loren J, Gordon WP, et al. TrkB inhibition by GNF-4256 slows growth and enhances chemotherapeutic efficacy in neuroblastoma xenografts. Cancer Chemother Pharmacol. 2015;75(1):131–41.

    CAS  PubMed  Google Scholar 

  23. Iyer R, Wehrmann L, Golden RL, Naraparaju K, Croucher JL, MacFarland SP, et al. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016;372(2):179–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Li Z, Zhang Y, Tong Y, Tong J, Thiele CJ. Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo. Cancer Biol Ther. 2015;16(3):477–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jaboin J, Kim CJ, Kaplan DR, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3′-kinase pathway. Cancer Res. 2002;62(22):6756–63.

    CAS  PubMed  Google Scholar 

  26. Jaboin J, Hong A, Kim CJ, Thiele CJ. Cisplatin-induced cytotoxicity is blocked by brain-derived neurotrophic factor activation of TrkB signal transduction path in neuroblastoma. Cancer Lett. 2003;193(1):109–14.

    CAS  PubMed  Google Scholar 

  27. Eberhart CG, Kaufman WE, Tihan T, Burger PC. Apoptosis, neuronal maturation, and neurotrophin expression within medulloblastoma nodules. J Neuropathol Exp Neurol. 2001;60(5):462–9.

    CAS  PubMed  Google Scholar 

  28. Kokunai T, Sawa H, Tamaki N. Functional analysis of trk proto-oncogene product in medulloblastoma cells. Neurol Med Chir (Tokyo). 1996;36(11):796–804.

    CAS  PubMed  Google Scholar 

  29. Muragaki Y, Chou TT, Kaplan DR, Trojanowski JQ, Lee VMY. Nerve growth factor induces apoptosis in human medulloblastoma cell lines that express TrkA receptors. J Neurosci. 1997;17(2):530–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Stephan H, Zakrzewski JL, Bölöni R, Grasemann C, Lohmann DR, Eggert A. Neurotrophin receptor expression in human primary retinoblastomas and retinoblastoma cell lines. Pediatr Blood Cancer. 2008;50(2):218–22.

    PubMed  Google Scholar 

  31. Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature. 1986;319(6056):743–8.

    CAS  PubMed  Google Scholar 

  32. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998;18(2):184–7.

    CAS  PubMed  Google Scholar 

  34. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018. https://doi.org/10.1200/PO.18.00183.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367–76.

    CAS  PubMed  Google Scholar 

  36. Church AJ, Calicchio ML, Nardi V, Skalova A, Pinto A, Dillon DA, et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Mod Pathol. 2018;31(3):463–73.

    CAS  PubMed  Google Scholar 

  37. Drilon A, Li G, Dogan S, Gounder M, Shen R, Arcila M, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol. 2016;27(5):920–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol. 2010;321(1):44–9.

    CAS  PubMed  Google Scholar 

  39. Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet. 2013;45(10):1141–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Davis JL, Lockwood CM, Stohr B, Boecking C, Al-Ibraheemi A, Dubois SG, et al. Expanding the spectrum of pediatric NTRK-rearranged mesenchymal tumors. Am J Surg Pathol. 2019;43(4):435–45.

    PubMed  Google Scholar 

  42. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):1–9.

    Google Scholar 

  43. Taylor J, Pavlick D, Yoshimi A, Marcelus C, Chung SS, Hechtman JF, et al. Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies. J Clin Invest. 2018;128(9):3819–25.

    PubMed  PubMed Central  Google Scholar 

  44. Rudzinski ER, Lockwood CM, Stohr BA, Vargas SO, Sheridan R, Black JO, et al. Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. Am J Surg Pathol. 2018;42(7):927–35.

    PubMed  Google Scholar 

  45. Hechtman JF, Benayed R, Hyman DM, Drilon A, Zehir A, Frosina D, et al. Pan-Trk Immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547–51.

    PubMed  PubMed Central  Google Scholar 

  46. Bender J, Anderson B, Bloom DA, Rabah R, McDougall R, Vats P, et al. Refractory and metastatic infantile fibrosarcoma harboring LMNA–NTRK1 fusion shows complete and durable response to crizotinib. Cold Spring Harb Mol Case Stud. 2019;5(1):1–10.

    Google Scholar 

  47. Pavlick D, Schrock AB, Malicki D, Stephens PJ, Kuo DJ, Ahn H, et al. Identification of NTRK fusions in pediatric mesenchymal tumors. Pediatr Blood Cancer. 2017;64(8):1–5.

    Google Scholar 

  48. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 2015;5(10):1049–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Minturn JE, Evans AE, Villablanca JG, Yanik GA, Park JR, Shusterman S, et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. Cancer Chemother Pharmacol. 2011;68(4):1057–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mossé YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–80.

    PubMed  PubMed Central  Google Scholar 

  51. Mossé YP, Voss SD, Lim MS, Rolland D, Minard CG, Fox E, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children’s Oncology Group Study. J Clin Oncol. 2017;35(28):3215–21.

    PubMed  PubMed Central  Google Scholar 

  52. Drilon A, Siena S, Ou S-HI, Patel M, Ahn MJ, Lee J. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase i trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Robinson GW, Gajjar AJ, Gauvain KM, Basu EM, Macy ME, Maese LD, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. J Clin Oncol. 2019;37(15_suppl):10009.

    Google Scholar 

  54. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, et al. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018;124(21):4241–7.

    CAS  PubMed  Google Scholar 

  56. Awad MM, Katayama R, McTigue M, Liu W, Deng Y-L, Brooun A, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013;368(25):2395–401.

    CAS  PubMed  Google Scholar 

  57. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6(10):1118–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363(18):1734–9.

    CAS  PubMed  Google Scholar 

  59. Russo M, Misale S, Wei G, Siravegna G, Crisafulli G, Lazzari L, et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 2016;6(1):36–44.

    CAS  PubMed  Google Scholar 

  60. Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior trk kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 2017;7(9):963–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hyman D, Kummar S, Farago A, Geoerger B, Mau-Sorensen M, Taylor M, et al. Abstract CT127: Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Cancer Res. 2019;79(13_suppl):CT127.

    Google Scholar 

  62. Drilon A, Ou SHI, Cho BC, Kim DW, Lee J, Lin JJ, et al. Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations. Cancer Discov. 2018;8(10):1227–36.

    CAS  PubMed  Google Scholar 

  63. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4(120):120ra17.

    PubMed  PubMed Central  Google Scholar 

  64. Cocco E, Schram AM, Kulick A, Misale S, Won HH, Yaeger R, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med. 2019;25(9):1422–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Drilon AE, DuBois SG, Farago AF, Geoerger B, Grilley-Olson JE, Hong DS, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J Clin Oncol. 2019;37(15_suppl):200.

    Google Scholar 

  66. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, et al. Entrectinib, a Pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther. 2016;15(4):628–39.

    CAS  PubMed  Google Scholar 

  67. Orbach D, Brennan B, De Paoli A, Gallego S, Mudry P, Francotte N, et al. Conservative strategy in infantile fibrosarcoma is possible: the European paediatric Soft tissue sarcoma Study Group experience. Eur J Cancer. 2016;57(February):1–9.

    PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Alyaa Al-Ibraheemi MD for providing the pathology image shown in the Figure.

Author information

Authors and Affiliations

  1. Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA

    David S. Shulman & Steven G. DuBois

Authors
  1. David S. Shulman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven G. DuBois
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven G. DuBois.

Ethics declarations

Funding

NIH Grant T32 CA136432-08 (David S. Shulman) and Alex’s Lemonade Stand Foundation Center of Excellence Grant (Steven G. DuBois, David S. Shulman). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or other funding agencies.

Conflict of interest

Steven G. DuBois reports travel expenses from Loxo Oncology, Roche, and Salarius and consulting fee from Loxo Oncology. David S. Shulman declares that he has no conflicts of interest that might be relevant to the contents of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shulman, D.S., DuBois, S.G. The Evolving Diagnostic and Treatment Landscape of NTRK-Fusion-Driven Pediatric Cancers. Pediatr Drugs 22, 189–197 (2020). https://doi.org/10.1007/s40272-020-00380-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-020-00380-9

Search

Navigation