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

Andrea Sartore-Bianchi, Elena Ardini, Roberta Bosotti, Alessio Amatu, Emanuele Valtorta, Alessio Somaschini, Laura Raddrizzani, Laura Palmeri, Patrizia Banfi, Erica Bonazzina, Sandra Misale, Giovanna Marrapese, Antonella Leone, Rachele Alzani, David Luo, Zachary Hornby, Jonathan Lim, Silvio Veronese, Angelo Vanzulli, Alberto BardelliMarcella Martignoni, Cristina Davite, Arturo Galvani, Antonella Isacchi, Salvatore Siena

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numberdjv306
JournalJournal of the National Cancer Institute
Volume108
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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