title: Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model.
abstract: Neuroblastoma (NB) is one of the most common and deadly childhood solid tumors. These tumors are characterized by clinical heterogeneity, from spontaneous regression to relentless progression, and the Trk family of neurotrophin receptors plays an important role in this heterogeneous behavior. We wanted to determine if entrectinib (RXDX-101, Ignyta, Inc.), an oral Pan-Trk, Alk and Ros1 inhibitor, was effective in our NB model. In vitro effects of entrectinib, either as a single agent or in combination with the chemotherapeutic agents Irinotecan (Irino) and Temozolomide (TMZ), were studied on an SH-SY5Y cell line stably transfected with TrkB. In vivo growth inhibition activity was studied in NB xenografts, again as a single agent or in combination with Irino-TMZ. Entrectinib significantly inhibited the growth of TrkB-expressing NB cells in vitro, and it significantly enhanced the growth inhibition of Irino-TMZ when used in combination. Single agent therapy resulted in significant tumor growth inhibition in animals treated with entrectinib compared to control animals [p < 0.0001 for event-free survival (EFS)]. Addition of entrectinib to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals [p < 0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ]. We show that entrectinib inhibits growth of TrkB expressing NB cells in vitro and in vivo, and that it enhances the efficacy of conventional chemotherapy in in vivo models. Our data suggest that entrectinib is a potent Trk inhibitor and should be tested in clinical trials for NBs and other Trk-expressing tumors.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Iyer
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Lea
authors.initials: L
authors.lastname: Wehrmann
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Golden
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Koumudi
authors.initials: K
authors.lastname: Naraparaju
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Croucher
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Suzanne P
authors.initials: SP
authors.lastname: MacFarland
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Guan
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Venkatadri
authors.initials: V
authors.lastname: Kolla
authors.affiliation: The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Wei
authors.affiliation: The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cam
authors.affiliation: The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hornby
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Ignyta Inc., San Diego, CA 92121, USA. Electronic address: brodeur@email.chop.edu.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Brodeur
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077146:Irinotecan; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D007191:Indazoles; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D000077146:Irinotecan; D003606:Dacarbazine; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; C000607349:entrectinib; D002166:Camptothecin; D000077204:Temozolomide
keywords: Entrectinib; Kinase inhibitor; NTRK2; Neuroblastoma; RXDX-101; TrkB