16 research outputs found
Design of a Retrovirus-Derived Vector for Expression and Transduction of Exogenous Genes in Mammalian Cells
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Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells
The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMPK (AMP kinase), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism
Exploring the Role of Bromine at C(10) of (+)-4-[2-[4-(8-Chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11( R
Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C
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Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS
Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic
The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition
Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase
An
affinity-based mass spectrometry screening technology was used
to identify novel binders to both nonphosphorylated and phosphorylated
ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue <b>1</b> that bound to both nonphosphorylated and phosphorylated
ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified
compound <b>4</b> as a novel, potent, and highly selective ERK1,2
inhibitor which not only demonstrated inhibition of phosphorylation
of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2
phosphorylation on the activation loop. X-ray cocrystallography revealed
that upon binding of compound <b>4</b> to ERK2, Tyr34 undergoes
a rotation (flip) along with a shift in the poly-Gly rich loop to
create a new binding pocket into which <b>4</b> can bind. This
new binding mode represents a novel mechanism by which high affinity
ATP-competitive compounds may achieve excellent kinase selectivity
Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.
Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations