title: Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer.
abstract: Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.
  
  
  CONCLUSIONS
  We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements.
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy. FIRC Institute of Molecular Oncology (IFOM), Milano, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Misale
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Ge
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Crisafulli
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lazzari
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corti
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rospo
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Novara
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mussolin
authors.affiliation: Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cam
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Roopal
authors.initials: R
authors.lastname: Patel
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Shoemaker
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Andrea Sartore
authors.initials: AS
authors.lastname: Bianchi
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy. Università degli Studi di Milano, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. Candiolo Cancer Institute, FPO, IRCCS, Torino, Italy. alberto.bardelli@unito.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D015321:Gene Rearrangement; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D020917:Receptor, trkA / Q000737:chemistry / Q000235:genetics*
chemical_list: D001549:Benzamides; D007191:Indazoles; C000611485:NTRK1 protein, human; D047428:Protein Kinase Inhibitors; D020917:Receptor, trkA; C000607349:entrectinib