Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer

Nat Commun. 2018 Sep 17;9(1):3787. doi: 10.1038/s41467-018-06162-9.

Abstract

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.

Publication types

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

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cadherins / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Loss of Heterozygosity
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mutation
  • Neoplasm Recurrence, Local
  • Small Cell Lung Carcinoma / drug therapy
  • Small Cell Lung Carcinoma / genetics*
  • Small Cell Lung Carcinoma / pathology
  • Whole Exome Sequencing
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / genetics*

Substances

  • APC protein, human
  • ASCL1 protein, human
  • Adenomatous Polyposis Coli Protein
  • Basic Helix-Loop-Helix Transcription Factors
  • CDH8 protein, human
  • Cadherins