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/debate

7 Citations (Scopus)

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

Fingerprint

Triple Negative Breast Neoplasms
Peptides
Neoplasms
Cell Fusion
Gene Expression Profiling
Therapeutics
Oncogenes
Inhibitory Concentration 50
Allografts
Proteins
Pharmacology
Apoptosis
Breast Neoplasms
Growth
Research

Cite this

Wang, Edina ; Sorolla, Anabel ; Cunningham, Paula T ; Bogdawa, Heique M ; Beck, Samuel ; Golden, Emily ; Dewhurst, Robert E ; Florez, Laura ; Cruickshank, Mark N ; Hoffmann, Katrin ; Hopkins, Richard M ; Kim, Jonghwan ; Woo, Andrew J ; Watt, Paul M ; Blancafort, Pilar. / Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers. In: Oncogene. 2018 ; Vol. 38, No. 1. pp. 140-150.
@article{41d90b8824114a9fb3687337d2b1d6d5,
title = "Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers",
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.",
author = "Edina Wang and Anabel Sorolla and Cunningham, {Paula T} and Bogdawa, {Heique M} and Samuel Beck and Emily Golden and Dewhurst, {Robert E} and Laura Florez and Cruickshank, {Mark N} and Katrin Hoffmann and Hopkins, {Richard M} and Jonghwan Kim and Woo, {Andrew J} and Watt, {Paul M} and Pilar Blancafort",
year = "2018",
month = "8",
day = "3",
doi = "10.1038/s41388-018-0421-y",
language = "English",
volume = "38",
pages = "140--150",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "1",

}

Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers. / Wang, Edina; Sorolla, Anabel; Cunningham, Paula T; Bogdawa, Heique M; Beck, Samuel; Golden, Emily; Dewhurst, Robert E; Florez, Laura; Cruickshank, Mark N; Hoffmann, Katrin; Hopkins, Richard M; Kim, Jonghwan; Woo, Andrew J; Watt, Paul M; Blancafort, Pilar.

In: Oncogene, Vol. 38, No. 1, 03.08.2018, p. 140-150.

Research output: Contribution to journalComment/debate

TY - JOUR

T1 - Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers

AU - Wang, Edina

AU - Sorolla, Anabel

AU - Cunningham, Paula T

AU - Bogdawa, Heique M

AU - Beck, Samuel

AU - Golden, Emily

AU - Dewhurst, Robert E

AU - Florez, Laura

AU - Cruickshank, Mark N

AU - Hoffmann, Katrin

AU - Hopkins, Richard M

AU - Kim, Jonghwan

AU - Woo, Andrew J

AU - Watt, Paul M

AU - Blancafort, Pilar

PY - 2018/8/3

Y1 - 2018/8/3

N2 - 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.

AB - 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.

U2 - 10.1038/s41388-018-0421-y

DO - 10.1038/s41388-018-0421-y

M3 - Comment/debate

VL - 38

SP - 140

EP - 150

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 1

ER -