title: Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer.
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.
authors.affiliation: 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).
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: 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).
authors.forename: Elena
authors.initials: E
authors.lastname: Ardini
authors.affiliation: 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).
authors.forename: Roberta
authors.initials: R
authors.lastname: Bosotti
authors.affiliation: 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).
authors.forename: Alessio
authors.initials: A
authors.lastname: Amatu
authors.affiliation: 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).
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.affiliation: 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).
authors.forename: Alessio
authors.initials: A
authors.lastname: Somaschini
authors.affiliation: 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).
authors.forename: Laura
authors.initials: L
authors.lastname: Raddrizzani
authors.affiliation: 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).
authors.forename: Laura
authors.initials: L
authors.lastname: Palmeri
authors.affiliation: 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).
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banfi
authors.affiliation: 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).
authors.forename: Erica
authors.initials: E
authors.lastname: Bonazzina
authors.affiliation: 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).
authors.forename: Sandra
authors.initials: S
authors.lastname: Misale
authors.affiliation: 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).
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marrapese
authors.affiliation: 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).
authors.forename: Antonella
authors.initials: A
authors.lastname: Leone
authors.affiliation: 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).
authors.forename: Rachele
authors.initials: R
authors.lastname: Alzani
authors.affiliation: 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).
authors.forename: David
authors.initials: D
authors.lastname: Luo
authors.affiliation: 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).
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hornby
authors.affiliation: 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).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lim
authors.affiliation: 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).
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.affiliation: 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).
authors.forename: Angelo
authors.initials: A
authors.lastname: Vanzulli
authors.affiliation: 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).
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: 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).
authors.forename: Marcella
authors.initials: M
authors.lastname: Martignoni
authors.affiliation: 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).
authors.forename: Cristina
authors.initials: C
authors.lastname: Davite
authors.affiliation: 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).
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.affiliation: 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).
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: 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.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D034904:Lamin Type A / Q000037:antagonists & inhibitors / Q000235:genetics*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D058990:Molecular Targeted Therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics*; D033921:Vesicular Transport Proteins
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D034904:Lamin Type A; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; C494847:LMNA protein, human; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C062333:ROS1 protein, human