title: Identification and characterization of RET fusions in advanced colorectal cancer.
abstract: There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, USA.
authors.forename: Anne-France
authors.initials: AF
authors.lastname: Le Rolle
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: The Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Garrett
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Seery
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sanford
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.|Albany Medical College, Albany, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, USA.
authors.forename: Vi K
authors.initials: VK
authors.lastname: Chiu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D056918:Nuclear Receptor Coactivators / Q000235:genetics; D010641:Phenotype; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: RET fusion kinase; RET kinase inhibitor; colorectal cancer; comprehensive genomic profiling