Research

BRCA1 Binds TERRA RNA and Suppresses R-Loop-Based Telomeric DNA damage (Nature Communications)

In a recent study, first author Jekaterina Vohhodina, PhD, and senior author David Livingston, MD, asked whether BRCA1 contributes to the maintenance of telomeres through TERRA-based R-loop regulation. TERRA is a product of RNA polymerase II (RNAPII)-transcribed telomeric DNA that participates in telomere length regulation and chromosome end protection. BRCA1 physically interacts with TERRA RNA in a cell cycle-dependent way on the formation of R-loops at telomeres. They also identified a specific domain of the BRCA1 protein responsible for its direct interaction with TERRA RNA, and observed that mutations in this region interfere with TERRA binding and trigger increased TERRA-based R-loop formation, resulting in telomeric replication stress and telomeric dysfunction. Study results might be relevant to potential telomere-based cancer therapies. Since targeting R-loops has been considered a tumor therapy approach, an excess of TERRA R-loops in BRCA1-deficient cells represents a potential target for R-loop-directed therapy for BRCA1 mutation carriers ...

Oral NF-κB Inhibitor Dimethylaminoparthenolide Delays Prostate Cancer Resistance to Androgen Receptor Inhibition (Molecular Cancer Research)

NF-κB activation has been linked to prostate cancer (PCa) progression and is commonly observed in castrate-resistant disease. NF-κB-driven resistance to androgen deprivation therapy (ADT) in PCa cells is suggested to be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Thus, preventing resistance to ADT may be achieved by utilizing NF-κB inhibitors. Dimethylaminoparthlide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic profiles in patients with heme malignancies including decrease of NF-κB in circulating leuchemic blasts. In a recent study in Molecular Cancer Research, first author Katherine Morel, PhD, and senior author Christopher Sweeney, MBBS, report that activation of NF-κB/p65 by castration in mouse and human PCa models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. DMAPT inhibits phosphorylated-p65 dependent upregulation of AR-V7 and delays PCa castration resistance ... 

ERK Signaling Mediates Resistance to Immunomodulatory Drugs in the Bone Marrow Microenvironment (Science Advances)

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. In this recent study published in Science Advances, first author Jiye Liu, PhD, and senior author Kenneth Andersen, MD, identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown/knockout in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal–regulated kinase (ERK) signaling. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Their studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM ...

Coming Soon: Our Quarterly Newsletter

Stay current with Dana-Farber technology news, transactions, patents, publications, events, and more.

• Subscribe now