Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

Cancer Cell. 2019 Jul 8;36(1):17-34.e7. doi: 10.1016/j.ccell.2019.06.005.

Abstract

Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies.

Keywords: Dependency Map (depmap); RNA interference screen; SCLC; TCGA; blood cancer; drug sensitivity screen; pan-cancer signatures; pharmacogenomics; small-cell neuroendocrine; transdifferentiation.

Publication types

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

MeSH terms

  • Carcinoma, Small Cell / diagnosis*
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / etiology*
  • Computational Biology / methods
  • DNA Copy Number Variations
  • Disease Susceptibility
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Hematologic Neoplasms / diagnosis*
  • Hematologic Neoplasms / drug therapy
  • Hematologic Neoplasms / etiology*
  • Humans
  • Mutation
  • Neuroendocrine Tumors / diagnosis*
  • Neuroendocrine Tumors / drug therapy
  • Neuroendocrine Tumors / etiology*
  • Phenotype*
  • Transcriptome