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Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage

Kai Song1, Jenna K Minami2,3, Arthur Huang2

  • 1Department of Bioengineering, University of California, Los Angeles, California.

Cancer Discovery
|December 21, 2021
PubMed

Insights

Focal amplifications (FA) in BRAF drive resistance to targeted therapies in melanoma. These amplifications exhibit plasticity, switching between genetic structures and responding to drug dosage, impacting treatment strategies.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Focal amplifications (FA) are a key mechanism for targeted therapy resistance in cancer.
  • Understanding the structural dynamics of FAs is crucial for overcoming treatment resistance.
  • BRAF amplifications are implicated in melanoma resistance to MAPK inhibitors (MAPKi).

Purpose of the Study:

  • To investigate the structure and dynamics of BRAF focal amplifications in a melanoma model of dual MAPKi resistance.
  • To explore the plasticity of these amplifications under varying MAPKi dosages.
  • To determine the therapeutic implications of BRAF FA plasticity, including ferroptosis sensitivity.

Main Methods:

  • Development of a melanoma model with BRAFV600 amplifications via extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR).
  • Analysis of mode switching between DM and HSR structures.
  • Assessment of drug addiction-driven structural loss of BRAF amplicons.
  • Evaluation of ferroptosis sensitivity in resistant cells.

Main Results:

  • Melanoma cells with BRAFV600E FAs showed mode switching between DMs and HSRs, driven by de novo genetic changes or selection.
  • HSR-harboring cells exhibited drug addiction-driven loss of BRAF amplicons upon dose reduction, demonstrating plasticity beyond ecDNAs.
  • FA mechanisms can synergize with kinase domain duplications and alternative splicing to enhance resistance.
  • BRAF FA-mediated dual MAPKi-resistant cells displayed increased sensitivity to proferroptotic drugs.

Conclusions:

  • BRAF focal amplifications in melanoma exhibit significant plasticity, switching between extrachromosomal DNA and homogenously staining regions under therapeutic pressure.
  • This amplicon plasticity, coupled with other genetic alterations, contributes to resistance against dual MAPK inhibitors.
  • BRAF amplification-driven resistance confers sensitivity to proferroptotic drugs, offering a potential therapeutic avenue beyond current targeted therapies.

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