Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers

Oncogene. 2019 Jan;38(1):140-150. doi: 10.1038/s41388-018-0421-y. Epub 2018 Aug 3.


Overexpression of MYC oncogene is highly prevalent in many malignancies such as aggressive triple-negative breast cancers (TNBCs) and it is associated with very poor outcome. Despite decades of research, attempts to effectively inhibit MYC, particularly with small molecules, still remain challenging due to the featureless nature of its protein structure. Herein, we describe the engineering of the dominant-negative MYC peptide (OmoMYC) linked to a functional penetrating 'Phylomer' peptide (FPPa) as a therapeutic strategy to inhibit MYC in TNBC. We found FPPa-OmoMYC to be a potent inducer of apoptosis (with IC50 from 1-2 µM) in TNBC cells with negligible effects in non-tumorigenic cells. Transcriptome analysis of FPPa-OmoMYC-treated cells indicated that the fusion protein inhibited MYC-dependent networks, inducing dynamic changes in transcriptional, metabolic, and apoptotic processes. We demonstrated the efficacy of FPPa-OmoMYC in inhibiting breast cancer growth when injected orthotopically in TNBC allografts. Lastly, we identified strong pharmacological synergisms between FPPa-OmoMYC and chemotherapeutic agents. This study highlights a novel therapeutic approach to target highly aggressive and chemoresistant MYC-activated cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Cell-Penetrating Peptides / administration & dosage
  • Cell-Penetrating Peptides / pharmacology*
  • Cell-Penetrating Peptides / therapeutic use
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Female
  • Genes, myc
  • Humans
  • Inhibitory Concentration 50
  • Leucine Zippers / genetics
  • Mice
  • Models, Molecular
  • Molecular Targeted Therapy / methods*
  • Mutation
  • Neoplasm Proteins / antagonists & inhibitors*
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacokinetics
  • Peptide Fragments / therapeutic use*
  • Peptide Library
  • Protein Conformation
  • Protein Engineering
  • Proto-Oncogene Proteins c-myc / administration & dosage
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / pharmacokinetics
  • Proto-Oncogene Proteins c-myc / therapeutic use*
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / therapeutic use*
  • Triple Negative Breast Neoplasms / drug therapy*


  • Cell-Penetrating Peptides
  • FPPa peptide
  • MYC protein, human
  • Neoplasm Proteins
  • Peptide Fragments
  • Peptide Library
  • Proto-Oncogene Proteins c-myc
  • Recombinant Fusion Proteins
  • omomyc protein