Preferential sensitivity to HDAC inhibitors in tumors with CREBBP mutation

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Malte Hellwig1,2, Daniel J Merk3,4, Beat Lutz5

  • 1Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Cancer Gene Therapy
|May 10, 2019
PubMed

Insights

Histone deacetylase inhibitors (HDACi) show promise for treating cancers with CREBBP gene mutations. HDACi were more effective in CREBBP-mutated small cell lung cancer and medulloblastoma cells compared to wild-type.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Mutations in the CREBBP gene, encoding a histone acetyltransferase (HAT), are frequent in cancers like small cell lung cancer (SCLC) and Sonic Hedgehog medulloblastoma (SHH MB).
  • Targeting these CREBBP alterations is a critical unmet need for effective cancer therapies.

Purpose of the Study:

  • To investigate the therapeutic potential of histone deacetylase inhibitors (HDACi) in CREBBP-mutated and wild-type cancers.
  • To evaluate HDACi efficacy in both SCLC and SHH medulloblastoma models.

Main Methods:

  • Utilized human SCLC cell lines and primary mouse tumor cells.
  • Employed genetically engineered mouse models for SHH medulloblastoma.
  • Assessed the effects of HDACi on cell proliferation and IC50 values in CREBBP wild-type and mutated tumor contexts.

Main Results:

  • CREBBP-mutated SCLC cells exhibited significantly lower IC50 values upon HDACi treatment compared to CREBBP wild-type cells.
  • HDACi demonstrated significant inhibitory effects on the proliferation of CREBBP-mutated SHH medulloblastoma cells, both in vitro and in vivo.
  • Tumors with CREBBP mutations showed greater sensitivity to HDACi compared to their wild-type counterparts.

Conclusions:

  • Histone deacetylase inhibitors represent a potential therapeutic strategy for cancers driven by CREBBP mutations.
  • These findings support the clinical investigation of HDACi for patients with CREBBP-mutated SCLC and SHH medulloblastoma.

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