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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Research Article

Mechanisms of entrectinib resistance in a neuroblastoma xenograft model

Suzanne P. MacFarland, Koumudi Naraparaju, Radhika Iyer, Peng Guan, Venkatadri Kolla, Yuxuan Hu, Kai Tan and Garrett M. Brodeur
Suzanne P. MacFarland
1Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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  • ORCID record for Suzanne P. MacFarland
Koumudi Naraparaju
1Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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Radhika Iyer
2Medical Affairs, Bayer Pharmaceuticals
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Peng Guan
1Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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Venkatadri Kolla
1Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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Yuxuan Hu
3School of Computer Science and Technology, Xidian University
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Kai Tan
1Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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Garrett M. Brodeur
1Pediatrics/Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania
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  • For correspondence: Brodeur@email.chop.edu
DOI: 10.1158/1535-7163.MCT-18-1044
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Abstract

TrkB with its ligand, brain-derived neurotrophic factor (BDNF), are overexpressed in the majority of high-risk neuroblastomas (NBs). Entrectinib is a novel pan-TRK, ALK, and ROS1 inhibitor that has shown excellent preclinical efficacy in NB xenograft models, and recently it has entered phase 1 trials in pediatric relapsed/refractory solid tumors. We examined entrectinib-resistant NB cell lines to identify mechanisms of resistance. Entrectinib-resistant cell lines were established from five NB xenografts initially sensitive to entrectinib therapy. Clonal cell lines were established in increasing concentrations of entrectinib and had >10X increase in IC50. Cell lines underwent genomic and proteomic analysis using whole-exome sequencing, RNA-Seq, and proteomic expression profiling with confirmatory RT-PCR and Western blot analysis. There was no evidence of NTRK2 (TrkB) gene mutation in any resistant cell lines. Inhibition of TrkB was maintained in all cell lines at increasing concentrations of entrectinib (target independent). PTEN pathway downregulation and ERK/MAPK pathway upregulation were demonstrated in all resistant cell lines. One of these clones also had increased IGF1R signaling, and two additional clones had increased P75 expression, which likely increased TrkB sensitivity to ligand. In conclusion, NB lines overexpressing TrkB developed resistance to entrectinib by multiple mechanisms, including activation of ERK/MAPK and downregulation of PTEN signaling. Individual cell lines also had IGF1R activation and increased P75 expression, allowing preservation of downstream TrkB signaling in the presence of entrectinib. An understanding of changes in patterns of expression can be used to inform multimodal therapy planning in using entrectinib in phase II/III trial planning.

  • Received September 24, 2018.
  • Revision received June 3, 2019.
  • Accepted December 12, 2019.
  • Copyright ©2019, American Association for Cancer Research.
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This OnlineFirst version was published on December 23, 2019
doi: 10.1158/1535-7163.MCT-18-1044

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Mechanisms of entrectinib resistance in a neuroblastoma xenograft model
Suzanne P. MacFarland, Koumudi Naraparaju, Radhika Iyer, Peng Guan, Venkatadri Kolla, Yuxuan Hu, Kai Tan and Garrett M. Brodeur
Mol Cancer Ther December 23 2019 DOI: 10.1158/1535-7163.MCT-18-1044

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Mechanisms of entrectinib resistance in a neuroblastoma xenograft model
Suzanne P. MacFarland, Koumudi Naraparaju, Radhika Iyer, Peng Guan, Venkatadri Kolla, Yuxuan Hu, Kai Tan and Garrett M. Brodeur
Mol Cancer Ther December 23 2019 DOI: 10.1158/1535-7163.MCT-18-1044
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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