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WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Amanpreet Kaur1, Jun Yi Stanley Lim1, Sugunavathi Sepramaniam2

  • 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.

EMBO Molecular Medicine
|March 4, 2021
PubMed

Insights

Wnt signaling supports cancer stem cells and DNA repair. Blocking Wnt with PORCN inhibitors creates a BRCA-like state, sensitizing Wnt-addicted cancers to DNA damaging agents like olaparib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Stem Cell Biology

Background:

  • Wnt signaling is crucial for adult stem cell maintenance and contributes to cancer chemotherapy resistance.
  • PORCN inhibitors, which block Wnt secretion, show promise in preclinical cancer models and are in clinical trials.
  • Wnt signaling's role in DNA repair mechanisms within stem cells and cancers is an area of active investigation.

Purpose of the Study:

  • To investigate potential combination therapies for Wnt-addicted cancers.
  • To elucidate the mechanistic link between Wnt signaling and DNA repair pathways.
  • To explore the role of Wnt signaling in maintaining genomic integrity in stem cells and cancer.

Main Methods:

  • Screening for synergistic drug combinations with Wnt inhibitors.
  • Utilizing PORCN inhibitors to block Wnt secretion.
  • Analyzing gene expression of homologous recombination and Fanconi anemia repair pathways.
  • Investigating the Wnt/β-catenin/MYBL2 signaling axis.
  • Examining gene expression in intestinal crypts and polyps.

Main Results:

  • Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers.
  • Wnt/β-catenin signaling positively regulates key DNA repair genes (BRCA1, FANCD2, RAD51) in Wnt-high cancers.
  • PORCN inhibitor treatment induces a BRCA-like state, suggesting impaired DNA repair.
  • This regulatory axis (Wnt/β-catenin/MYBL2) is conserved in intestinal stem cells and upregulated in polyps.
  • Wnt signaling enhances DNA repair to maintain genomic integrity in stem cells and cancers.

Conclusions:

  • Wnt/β-catenin signaling promotes DNA repair, contributing to genomic stability in stem cells and cancers.
  • Blocking Wnt signaling may sensitize cancers to DNA damaging agents, including radiation therapy.
  • This study reveals a novel therapeutic strategy by combining Wnt inhibition with DNA damaging agents for cancer treatment.
Keywords:
BRCA1DNA repairETC-1922159FANCD2homologous recombination

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