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Epigenetic modulation reveals differentiation state specificity of oncogene addiction

Mehwish Khaliq1, Mohan Manikkam1, Elisabeth D Martinez2,3

  • 1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.

Nature Communications
|March 22, 2021
PubMed

Insights

Scientists screened epigenetic compounds to overcome resistance to MAPK inhibitors in melanoma. They identified epigenetic drug classes targeting specific cell states, improving anti-tumor efficacy based on differentiation and MAPK activity.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacology

Background:

  • The MAPK signaling pathway is a key target for BRAF-mutant melanoma treatment.
  • Epigenetic plasticity causes cell variability, reducing MAPK inhibitor efficacy.
  • Identifying regulators of this variability is crucial for improving melanoma therapy.

Purpose of the Study:

  • To screen epigenetic compounds for their ability to modulate MAPK inhibitor efficacy in melanoma.
  • To identify specific epigenetic targets and drug classes that overcome treatment resistance.
  • To correlate anti-tumor efficacy with melanoma cell differentiation state and MAPK activity.

Main Methods:

  • Screening of 276 epigenetic-modifying compounds alone and with MAPK inhibitors.
  • Utilizing genetically diverse and isogenic melanoma cell populations.
  • Employing single-cell analysis and multivariate modeling.

Main Results:

  • Identified three classes of epigenetic inhibitors targeting KDM1A, KDM4B, or BET bromodomain proteins.
  • Demonstrated that anti-tumor efficacy is predictable based on melanoma cell differentiation and MAPK activity.
  • Showed melanocytes are insensitive to these epigenetic inhibitors.

Conclusions:

  • Epigenetic drug screening can identify novel therapeutic strategies for melanoma.
  • Targeting specific epigenetic states offers a way to overcome MAPK inhibitor resistance.
  • Tumor cell differentiation state is a key factor in predicting response to epigenetic therapies.

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