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

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 rearrangeme...

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Detalles Bibliográficos
Autores principales: Sartore-Bianchi, Andrea, Ardini, Elena, Bosotti, Roberta, Amatu, Alessio, Valtorta, Emanuele, Somaschini, Alessio, Raddrizzani, Laura, Palmeri, Laura, Banfi, Patrizia, Bonazzina, Erica, Misale, Sandra, Marrapese, Giovanna, Leone, Antonella, Alzani, Rachele, Luo, David, Hornby, Zachary, Lim, Jonathan, Veronese, Silvio, Vanzulli, Angelo, Bardelli, Alberto, Martignoni, Marcella, Davite, Cristina, Galvani, Arturo, Isacchi, Antonella, Siena, Salvatore
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712682/
https://www.ncbi.nlm.nih.gov/pubmed/26563355
http://dx.doi.org/10.1093/jnci/djv306
Descripción
Sumario: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.