title: Integrated genetic and pharmacologic interrogation of rare cancers.
abstract: Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.|Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Andrew L
authors.identifier: 0000-0003-0374-1667
authors.initials: AL
authors.lastname: Hong
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Yuen-Yi
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, 500 Main Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Jonas
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, 500 Main Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Jaime H
authors.initials: JH
authors.lastname: Cheah
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Kynnap
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.|Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Mihir B
authors.initials: MB
authors.lastname: Doshi
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Coyin
authors.initials: C
authors.lastname: Oh
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Meyer
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Alanna J
authors.initials: AJ
authors.lastname: Church
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Shubhroz
authors.initials: S
authors.lastname: Gill
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Bielski
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Keskula
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.|Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Alma
authors.initials: A
authors.lastname: Imamovic
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Howell
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Aviad
authors.identifier: 0000-0002-3797-1877
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Crompton
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.|Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: van Hummelen
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, 500 Main Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cima
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, 500 Main Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Langer
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.|Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Stuart L
authors.identifier: 0000-0003-1922-7558
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.|Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Jesse S
authors.identifier: 0000-0002-6795-6336
authors.initials: JS
authors.lastname: Boehm
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D064113:CRISPR-Cas Systems; D002453:Cell Cycle; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D004317:Doxorubicin / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D059472:Exome; D005260:Female; D023281:Genomics; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage; D028884:Karyopherins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D034622:RNA Interference; D035583:Rare Diseases / Q000188:drug therapy / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014230:Triazoles / Q000008:administration & dosage; D000097606:Exportin 1 Protein
chemical_list: D051358:Cyclin-Dependent Kinase 4; D004317:Doxorubicin; D006834:Hydrazines; D028884:Karyopherins; D010879:Piperazines; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C585161:selinexor; C495900:CDK4 protein, human; C500026:palbociclib