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Ref Type Journal Article
PMID (27256375)
Authors Pérez-Peña J, Serrano-Heras G, Montero JC, Corrales-Sánchez V, Pandiella A, Ocaña A
Title In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment.
Journal Molecular cancer therapeutics
Vol 15
Issue 8
Date 2016 Aug
URL
Abstract Text Triple-negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy, and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain-containing proteins affecting the expression of transcription factors, therefore modifying the expression of relevant oncogenic genes. In the present article, by using an in silico approach, we have identified the expression of upregulated transcription factors in TNBC compared with normal breast. Treatment with JQ1, a well-characterized BET inhibitor, modified some transcription factors, including DEP domain containing 1 (DEPDC), Forkhead box M1 (FOXM1), and Lim domain only 4 (LM04). In cell line models, administration of JQ1 or OTX015, another BET inhibitor, produced a significant antiproliferative effect and synergized with chemotherapies. Biochemical evaluation demonstrated an arrest at G1 as the main mechanism of action with a clear increase of p27. Addition of these compounds to chemotherapy induced apoptosis compared to each agent given alone. Evaluation of JQ1 in xenografted tumors in nude mice showed a profound antitumoral effect with a reduction of DEPDC, FOXM1, and LM04, in addition to an increase of p27. Globally, our data demonstrate the antitumor effect of this new family of compounds in TNBC, paving the way for its future clinical development. Mol Cancer Ther; 15(8); 1823-33. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown triple-receptor negative breast cancer not applicable Cisplatin + JQ1 Preclinical - Cell culture Actionable In a preclinical study, the addition of JQ1 to Platinol (cisplatin) resulted in a synergistic effect in triple-receptor negative breast cancer cells in culture (PMID: 27256375). 27256375
Unknown unknown triple-receptor negative breast cancer not applicable Carboplatin + JQ1 Preclinical - Cell culture Actionable In a preclinical study, the addition of JQ1 to Paraplatin (carboplatin) resulted in a synergistic effect in triple-receptor negative breast cancer cells in culture (PMID: 27256375). 27256375
Unknown unknown triple-receptor negative breast cancer not applicable JQ1 + Vinorelbine Preclinical - Cell culture Actionable In a preclinical study, the addition of JQ1 to Taxotere (docetaxel) resulted in a synergistic effect in triple-receptor negative breast cancer cells in culture (PMID: 27256375). 27256375
Unknown unknown triple-receptor negative breast cancer not applicable JQ1 Preclinical - Cell line xenograft Actionable In a preclinical study, triple-receptor negative breast cancer cells demonstrated sensitivity to treatment with JQ1, resulting in decrease cell proliferation and cell cycle arrest in culture and tumor growth inhibition in cell line xenograft models (PMID: 27256375). 27256375
Unknown unknown triple-receptor negative breast cancer not applicable Docetaxel + JQ1 Preclinical - Cell culture Actionable In a preclinical study, the addition of JQ1 to Taxotere (docetaxel) resulted in a synergistic effect in triple-receptor negative breast cancer cells in culture (PMID: 27256375). 27256375
Unknown unknown triple-receptor negative breast cancer not applicable Birabresib Preclinical - Cell culture Actionable In a preclinical study, triple-receptor negative breast cancer cells demonstrated sensitivity to treatment with Birabresib (OTX015), resulting in decreased cell proliferation in culture (PMID: 27256375). 27256375