Advertisement

Larotrectinib (LOXO-101)

  • Stephanie Berger
  • Uwe M. Martens
  • Sylvia Bochum
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 211)

Abstract

One of the most challenging issues in oncology research and treatment is identifying oncogenic drivers within an individual patient’s tumor which can be directly targeted by a clinically available therapeutic drug. In this context, gene fusions as one important example of genetic aberrations leading to carcinogenesis follow the widely accepted concept that cell growth and proliferation are driven by the accomplished fusion (usually involving former proto-oncogenes) and may therefore be successfully inhibited by substances directed against the fusion. This concept has already been established with oncogenic gene fusions like BCR-ABL in chronic myelogenous leukemia (CML) or anaplastic lymphoma kinase (ALK) in lung cancer, including special tyrosine kinase inhibitors (TKIs) which are able to block the activation of the depending downstream proliferation pathways and, consequently, tumor growth. During the last decade, the NTRK1, 2, and 3 genes, encoding the TRKA, B, and C proteins, have attracted increasing attention as another significant and targetable gene fusion in a variety of cancers. Several TRK inhibitors have been developed, and one of them, Larotrectinib (formerly known as LOXO-101), represents an orally available, selective inhibitor of the TRK receptor family that has already shown substantial clinical benefit in both pediatric and adult patients harboring an NTRK gene fusion over the last few years.

Keywords

NTRK genes TRK receptor family Larotrectinib LOXO-101 

References

  1. Ardini E, Bosotti R, Borgia A, De Ponti C et al (2014) The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol Oncol 8:1495–1507CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bollig-Fischer A, Michelhaugh S et al (2015) Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics. Oncotarget 6(16):14614–14624CrossRefPubMedPubMedCentralGoogle Scholar
  3. Burris H, Hong D, Shaw A, Doebele R, Bauer T et al (2015a) Pharmacokinetics (PK) of LOXO-101 during the first-in-human phase I study in patients with advanced solid tumors—interim update. Poster, presented at the AACR annual meeting 2015, PennsylvaniaGoogle Scholar
  4. Burris H, Brose M, Shaw A et al (2015b) A first-in-human study of LOXO-101, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family. J Clin Oncol 33(suppl): abstract TPS2624Google Scholar
  5. Califano R, Abidin A, Tariq N et al (2015) Beyond EGFR and ALK inhibition: unravelling and exploiting novel genetic alternations in advanced non small-cell lung cancer. Cancer Treat Rev 41(5):401–411CrossRefPubMedGoogle Scholar
  6. Chao M (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309CrossRefPubMedGoogle Scholar
  7. Coppola V, Barrick C, Southon E, Celeste A et al (2004) Ablation of TrkA function in the immune system causes B cell abnormalities. Development 131:5185–5195CrossRefPubMedGoogle Scholar
  8. Doebele R, Davis L, Vaishnavi A, Le A, Estrada-Bernal et al (2015) An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov 5:1049–1057Google Scholar
  9. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22CrossRefGoogle Scholar
  10. Drilon A, Nagasubramanian R, Blake J, Ku N et al (2017) A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov 7:963–972CrossRefPubMedPubMedCentralGoogle Scholar
  11. Farago A, Le L, Zheng Z, Muzikansky A, Drilon A et al (2015) Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer. J Thorac Oncol 10:1670–1674CrossRefPubMedPubMedCentralGoogle Scholar
  12. Frattini V, Trifonov V, Chan J et al (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45:1141–1149CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gao J, Aksoy B et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1Google Scholar
  14. Hong D, Brose M, Doebele R, Shaw A et al (2015) Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. Mol Cancer Ther 14(12 Suppl2): abstract nr PR 13Google Scholar
  15. Hong D, Farago A, Brose M et al (2016) Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. American Association for Cancer Research 2016 annual meetingGoogle Scholar
  16. Hyman DM et al (2017) The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TKR) inhibitor, in adult and pediatric TRK fusion cancers. In: Proceedings from the 2017 ASCO annual meeting, Chicago, Illinois, 2–6 June 2017. Abstract LBA2501, J Clin Oncol 35(suppl)Google Scholar
  17. Kaplan D, Martin-Zanca D, Parad L (1991) Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350:158–160CrossRefPubMedGoogle Scholar
  18. Khotskaya Y, Vijaykumar R, Farago A, Mills Shaw K, Merci-Bernstam F, Hong D (2017) Targeting TRK family proteins in cancer. Pharmacol Ther 173:58–66CrossRefPubMedGoogle Scholar
  19. Klein R, Jing S, Nanduri V, Barbacid M (1991) The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65:189–197CrossRefPubMedGoogle Scholar
  20. Knezevich S, McFadden D, Tao W, Lim J, Sorensen P (1998) A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18:184–187CrossRefPubMedPubMedCentralGoogle Scholar
  21. Laetsch T et al (2017) A pediatric phase I study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family. In: Proceedings from the 2017 ASCO annual meeting, Chicago, Illinois, 2–6 June 2017. Abstract 10510Google Scholar
  22. Martin-Zanca D, Hughes S, Barbacid M (1986) A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 319:743–748CrossRefPubMedGoogle Scholar
  23. Miranda C, Mazzoni M, Sensi M, Pierotti M, Greco A (2014) Functional characterization of NTRK1 mutations identified in melanoma. Genes Chromosom Cancer 53:875–880CrossRefPubMedGoogle Scholar
  24. Nagasubramanian R, Wei J, Gordon P, Rastatter J, Cox M, Pappo A (2016) Infantile fibrosarcoma with NTRK3-ETV6 fusion successfully treated with the tropomyosin-related kinase inhibitor LOXO-101. Pediatr Blood Cancer 63:1468–1470CrossRefPubMedPubMedCentralGoogle Scholar
  25. Okimoto R, Bivona T (2016) Tracking down response and resistance to TRK inhibitors. Cancer Discov 6:14–16CrossRefPubMedPubMedCentralGoogle Scholar
  26. Ricciuti B, Brambilla M, Metro G, Baglivo S, Matocci R, Pirro M, Chiari R (2017) Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence. Med Oncol 34:105CrossRefPubMedGoogle Scholar
  27. Roccato E, Miranda C, Ranzi V, Gishizki M, Pierotti M, Greco A (2002) Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc. Br J Cancer 87:645–653CrossRefPubMedPubMedCentralGoogle Scholar
  28. Ross J, Wang K, Gay L, Al-Rohil R, Rand J, Jones D et al (2014) New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19:235–242CrossRefPubMedPubMedCentralGoogle Scholar
  29. Rubin J, Segal R (2003) Growth, survival and migration: the Trk to cancer. Cancer Treat Res 115:1–18PubMedGoogle Scholar
  30. Shukla N, Roberts S, Baki M, Mushtaq Q, Goss P et al (2017) Successful targeted therapy of refractory pediatric ETV6-NTRK3 fusion-positive secretory breast carcinoma. JCO Precis Oncol, published online, ascopubs.org/journal/poGoogle Scholar
  31. Snider W (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638CrossRefPubMedGoogle Scholar
  32. Soda M, Choi Y, Enomoto M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566CrossRefPubMedGoogle Scholar
  33. Stransky N, Cerami E, Schalm S, Kim J, Lengauer C (2014) The landscape of kinase fusions in cancer. Nat Commun 5:4846CrossRefPubMedPubMedCentralGoogle Scholar
  34. Tacconelli A, Farina A, Cappabianca L, Desantis G, Tessitore A, Vetuschi A et al (2004) TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6:347–360CrossRefGoogle Scholar
  35. Tognon C, Knezevich S, Huntsman D (2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367–376CrossRefPubMedGoogle Scholar
  36. Vaishnavi A, Capelletti M, Le A, Kako S, Butaney M et al (2013) Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19(11):1469–1472CrossRefPubMedPubMedCentralGoogle Scholar
  37. Vaishnavi A, Le A, Doebele R (2015) TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 5:25–34CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Stephanie Berger
    • 1
  • Uwe M. Martens
    • 1
  • Sylvia Bochum
    • 1
  1. 1.Cancer Center Heilbronn-FrankenMOLIT Institute, SLK-Kliniken Heilbronn GmbHHeilbronnGermany

Personalised recommendations