title: Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer.
abstract: BACKGROUND
  Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies.
  
  
  METHODS
  We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR.
  
  
  RESULTS
  A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response.
  
  
  CONCLUSIONS
  We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Amatu
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Somaschini
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cerea
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bosotti
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Buonandi
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marrapese
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.affiliation: Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.
authors.forename: David
authors.initials: D
authors.lastname: Luo
authors.affiliation: Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hornby
authors.affiliation: Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.
authors.forename: Pratik
authors.initials: P
authors.lastname: Multani
authors.affiliation: Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shoemaker
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Calogero
authors.initials: C
authors.lastname: Lauricella
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giannetta
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Maiolani
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vanzulli
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ardini
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.|Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001221:Aspartate Carbamoyltransferase / Q000235:genetics*; D001549:Benzamides / Q000627:therapeutic use*; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004080:Dihydroorotase / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C033626:CAD trifunctional enzyme; D007191:Indazoles; D001221:Aspartate Carbamoyltransferase; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C000607349:entrectinib