Integrated Genetic and Pharmacologic Interrogation of Rare Cancers

Nat Commun. 2016 Jun 22;7:11987. doi: 10.1038/ncomms11987.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • CRISPR-Cas Systems
  • Cell Cycle
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / genetics*
  • Doxorubicin / administration & dosage
  • Drug Screening Assays, Antitumor
  • Exome
  • Female
  • Genomics
  • Humans
  • Hydrazines / administration & dosage
  • Karyopherins / genetics*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local
  • Neoplasm Transplantation
  • Piperazines / administration & dosage
  • Pyridines / administration & dosage
  • RNA Interference
  • Rare Diseases / drug therapy
  • Rare Diseases / genetics*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Sarcoma / drug therapy
  • Sarcoma / genetics*
  • Sequence Analysis, RNA
  • Triazoles / administration & dosage

Substances

  • Hydrazines
  • Karyopherins
  • Piperazines
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • Triazoles
  • exportin 1 protein
  • selinexor
  • Doxorubicin
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • palbociclib