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

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

Author information

1
Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy (ASB, AA, EV, LP, EB, GM, SV, AV, SS); Nerviano Medical Sciences S.r.l Nerviano, Milan, Italy (EA, RB, AS, LR, PB, AL, RA, AG, AI); Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy (SM, AB); University of Torino, Department of Oncology, Candiolo, Torino, Italy (AB); FIRC Institute of Molecular Oncology (IFOM), Milano, Italy (SM); Ignyta, Inc., San Diego, CA (DL, ZH, JL); Clioss S.r.l. Nerviano, Milan, Italy (MM, CD); Università degli Studi di Milano, Milan, Italy (SS).
2
Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy (ASB, AA, EV, LP, EB, GM, SV, AV, SS); Nerviano Medical Sciences S.r.l Nerviano, Milan, Italy (EA, RB, AS, LR, PB, AL, RA, AG, AI); Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy (SM, AB); University of Torino, Department of Oncology, Candiolo, Torino, Italy (AB); FIRC Institute of Molecular Oncology (IFOM), Milano, Italy (SM); Ignyta, Inc., San Diego, CA (DL, ZH, JL); Clioss S.r.l. Nerviano, Milan, Italy (MM, CD); Università degli Studi di Milano, Milan, Italy (SS). salvatore.siena@ospedaleniguarda.it.

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.

PMID:
26563355
PMCID:
PMC4712682
DOI:
10.1093/jnci/djv306
[Indexed for MEDLINE]
Free PMC Article

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