Novel strategy to inhibit the oncogenic transcription factor c-Myc in triple-negative breast cancer

Rita Mejzini

Triple-negative breast cancer (TNBC), characterised by the minimal expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2), is an aggressive clinical phenotype. Its expression profile means it is not amenable to hormone therapy or HER-2 directed treatments with systemic treatment options limited to cytotoxic chemotherapy. There is therefore an unmet need for new targeted treatments for this cancer subtype. Transcription factor c-Myc (Myc) is frequently deregulated in these cases and is implicated in breast cancer development and progression. Omomyc is a peptide able to interfere with the protein-protein interactions of Myc, inhibiting transcriptional activation of its target genes. Here I report on the use of a new cell penetrating peptide (CPP), 1746, to deliver Omomyc to TNBC cells and on a truncated version of the Omomyc peptide (Omi) linked to 1746 (1746-Omi) and the traditional CPP Penetratin (Penetratin-Omi). I found 1746-Omomyc reduced the viability of TNBC cells overexpressing Myc by reducing proliferation. The truncated peptides were not as potent but demonstrated greater selectivity towards cancer cells. Penetratin-Omi had a greater activity than 1746-Omi and reduced cell viability primarily through cell death rather than reduced proliferation. The effect of 1746-Omomyc and Penetratin-Omi on the regulation of selected downstream Myc targets was determined by qRT-PCR and was consistent with but does not confirm Myc inhibition. This demonstrates the potential of 1746-Omomyc as an effective Myc inhibitor in TNBC. The shortening of Omomyc’s sequence reduced the peptides activity with much higher concentrations of 1746-Omi and Penetratin-Omi required to effect cancer cell viability. The mechanism of action of Penetratin-Omi also differed from 1746-Omomyc, indicating the possibility of a cargo-dependent cytotoxicity at high concentrations. Improving the design of the peptides could increase efficiency and reduce the possibility of any cytotoxic side effects.

Novel strategy to inhibit the oncogenic transcription factor c-Myc in triple-negative breast cancer

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