Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer

J Natl Cancer Inst. 2015 Nov 12;108(1):djv306. doi: 10.1093/jnci/djv306. Print 2016 Jan.

Abstract

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Drug Administration Schedule
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Fusion*
  • Gene Rearrangement*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Lamin Type A / antagonists & inhibitors
  • Lamin Type A / genetics*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / secondary
  • Molecular Targeted Therapy
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proteins / antagonists & inhibitors
  • Proteins / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor, trkA / antagonists & inhibitors
  • Receptor, trkA / genetics*

Substances

  • Antineoplastic Agents
  • LMNA protein, human
  • Lamin Type A
  • Proteins
  • Proto-Oncogene Proteins
  • TFG protein, human
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • ROS1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA