Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer.

Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development.

Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer.

The inhibition of bromo- and extraterminal domains (BET) has shown an anti-proliferative effect in triple negative breast cancer (TNBC). In this article we explore mechanisms of resistance to BET inhibitors (BETi) in TNBC, with the aim of identifying novel ways to overcome such resistance. Two cellular models of acquired resistance to the BET inhibitor JQ1 were generated using a pulsed treatment strategy.

Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer.

Purpose: Triple negative breast cancers (TNBCs) are enriched in cells bearing stem-like features, i.e., cancer stem cells (CSCs), which underlie cancer progression.

Pharmacological screening and transcriptomic functional analyses identify a synergistic interaction between dasatinib and olaparib in triple-negative breast cancer.

Identification of druggable vulnerabilities is a main objective in triple-negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and studies with semi-solid media were performed to explore the activity of the combinations.

Screening and Preliminary Biochemical and Biological Studies of [RuCl(-cymene)(,-bis(diphenylphosphino)-isopropylamine)][BF] in Breast Cancer Models.

Breast cancer is the second leading cause of cancer death worldwide. Despite progress in drug discovery, identification of the correct population is the limiting factor to develop new compounds in the clinical setting. Therefore, the aim of this study is to evaluate the effects of a new metallodrug, [RuCl(-cymene)(,-bis(diphenylphosphino)-isopropylamine)][BF] (), as a lead pnp-Ru compound by screening and preliminary biochemical and biological studies in different breast cancer subtypes.

Mapping Bromodomains in breast cancer and association with clinical outcome.

A specific family of proteins that participate in epigenetic regulation is the bromodomain (BRD) family of proteins. In this work, we aimed to explore the expression of the BRD family at a transcriptomic level in breast cancer, and its association with patient survival. mRNA level data from normal breast and tumor tissues were extracted from public datasets.

Transcriptome evolution from breast epithelial cells to basal-like tumors.

In breast cancer, it is unclear the functional modifications at a transcriptomic level that are associated with the evolution from epithelial cells and ductal carcinoma (DCIS) to basal-like tumors. By applying weighted gene co-expression network analysis (WGCNA), we identified 17 gene co-expression modules in normal, DCIS and basal-like tumor samples. We then correlated the expression pattern of these gene modules with disease progression from normal to basal-like tumours and found eight modules exhibiting a high and statistically significant correlation.

Ubiquitin-conjugating enzyme E2T (UBE2T) and denticleless protein homolog (DTL) are linked to poor outcome in breast and lung cancers.

Protein ubiquitination and degradation represent druggable vulnerabilities of cancer cells. We used gene expression and functional annotation analyses to identify genes in the ubiquitin pathway which are differentially expressed between normal breast and basal-like tumors. With this approach we identified 16 ubiquitin related genes overexpressed in basal-like breast cancers compared with normal breast.

Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer.

Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G arrest. In our study, by using an approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors.

Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors.

Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype.

DNA-damage related genes and clinical outcome in hormone receptor positive breast cancer.

Background: Control of DNA damage is frequently deregulated in solid tumors. Upregulation of genes within this process can be indicative of a more aggressive phenotype and linked with worse outcome. In the present article we identify DNA damage related genes associated with worse outcome in breast cancer.

In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment.

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.

Circulating DNA and Survival in Solid Tumors.

Background: The ability to undertake molecular analysis to inform on prognosis and predictors of response to therapy is limited by accessibility of tissue. Measurement of total circulating free DNA (cfDNA) or circulating tumor DNA (ctDNA) in peripheral blood may allow easier access to tumor material and help to predict clinical outcomes.

Methods: A systematic review of electronic databases identified publications exploring the association between cfDNA or ctDNA and overall survival (OS) in solid tumors.

Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses.

Background: Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents.

Methods And Findings: Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed.

Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors.

Protein kinases play a central role in the oncogenesis of colorectal tumors and are attractive druggable targets. Detection of activated kinases within a tumor could open avenues for drug selection and optimization of new kinase inhibitors. By using a phosphokinase arrays with human colorectal tumors we identified activated kinases, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and STAT, among others.

Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer.

Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC.

Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis.

Background: Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear.