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Mesenchymal subtype neuroblastomas are addicted to TGF-βR2/HMGCR-driven protein geranylgeranylation

Michael E Stokes1, Jonnell Candice Small1,2, Alessandro Vasciaveo3

  • 1Department of Biological Sciences, Columbia University, New York City, NY, 10027, USA.

Scientific Reports
|July 3, 2020
PubMed

Insights

Targeted cancer drug discovery faces challenges. Researchers identified metabolic vulnerabilities in neuroblastoma (NBL) subtypes, revealing lovastatin as a potential therapy for mesenchymal NBL by targeting the mevalonate pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Identifying targeted cancer therapies with high therapeutic indices remains a significant challenge in drug discovery.
  • Neuroblastoma (NBL) is a pediatric cancer with distinct subtypes, necessitating subtype-specific therapeutic strategies.

Purpose of the Study:

  • To identify subtype-specific metabolic dependencies in neuroblastoma (NBL) using chemical library screening.
  • To discover novel therapeutic targets and biomarkers for NBL subtypes.

Main Methods:

  • Screening of chemical libraries across mesenchymal (MESN) and MYCN-amplified (MYCNA) NBL cell models.
  • Utilizing lovastatin, a mevalonate biosynthesis inhibitor, to assess pathway dependencies.
  • Analyzing gene expression profiles to identify regulatory pathways and potential biomarkers.

Main Results:

  • The mevalonate and folate biosynthetic pathways were identified as MESN-selective dependencies.
  • Lovastatin selectively inhibited protein prenylation and induced apoptosis in MESN cells, correlating with HMGCR expression as a biomarker for statin sensitivity.
  • A TGFBR2 signaling axis regulating HMGCR was identified, representing an actionable addiction in MESN-NBL.

Conclusions:

  • Metabolic profiling of NBL subtypes can reveal distinct dependencies and guide targeted therapy development.
  • Targeting the mevalonate pathway with statins, like lovastatin, shows promise for treating MESN-NBL, with HMGCR expression serving as a predictive biomarker.
  • The TGFBR2-HMGCR axis represents a novel therapeutic vulnerability in MESN-NBL.

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