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

Edina Wang, Anabel Sorolla, Paula T Cunningham, Heique M Bogdawa, Samuel Beck, Emily Golden, Robert E Dewhurst, Laura Florez, Mark N Cruickshank, Katrin Hoffmann, Richard M Hopkins, Jonghwan Kim, Andrew J Woo, Paul M Watt, Pilar Blancafort

Research output: Contribution to journalComment/debatepeer-review

33 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)140-150
JournalOncogene
Volume38
Issue number1
DOIs
Publication statusE-pub ahead of print - 3 Aug 2018

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