A5074233996- Hippo pathway signaling and YAP/TAZ
- Plant Surface Properties and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Melanoma and MAPK Pathways
- Pancreatic and Hepatic Oncology Research
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- CRISPR and Genetic Engineering
- Colorectal Cancer Treatments and Studies
- Cancer-related gene regulation
- Caveolin-1 and cellular processes
- Phagocytosis and Immune Regulation
- Peroxisome Proliferator-Activated Receptors
- Microtubule and mitosis dynamics
- Metabolism and Genetic Disorders
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- Cellular Mechanics and Interactions
- Cancer, Hypoxia, and Metabolism
- Protein Tyrosine Phosphatases
University of North Carolina at Chapel Hill
2023-2025
UNC Lineberger Comprehensive Cancer Center
2024
Segeberger Kliniken
2024
How the
To delineate the mechanisms by which ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We that share near-identical signaling transforming outputs KRAS-regulated is driven nearly completely ERK. identified 4666 phosphosites on 2123 proteins, of 79 66%, respectively, were not previously associated with ERK, substantially expanding depth breadth phosphorylation events revealing...
Abstract Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to long-term efficacy of direct inhibitors KRASG12C mutant in cancer. To identify potential mechanisms resistance, we applied a CRISPR/Cas9 loss-of-function screen observed loss multiple components Hippo tumor suppressor pathway, which acts suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired antiproliferative proapoptotic effects inhibitor (G12Ci) treatment...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux dependency, concurrent treatment with nonspecific autophagy inhibitor chloroquine (CQ) ERK-MAPK inhibitors can synergistically block PDAC However, CQ limited in terms specificity potency. To find alternative anti-autophagy strategies, here we performed a CRISPR-Cas9 loss-of-function screen cell lines that identified...
Abstract Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in cancers harboring genomic deletions of the MTAP gene, which encodes enzyme methylthioadenosine phosphorylase. Approximately one four pancreatic ductal adenocarcinoma (PDAC) cases harbor homozygous deletion gene (MTAP-del), providing promising novel targeted therapy for PDAC. The (MTA)-cooperative PRMT5 inhibitor BMS-986504 (previously known as MRTX1719) leverages elevated MTA levels present MTAP-del tumors...
<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by <i>KRAS</i>- and autophagy-dependent growth. Inhibition of the KRAS–RAF–MEK–ERK pathway enhances autophagic flux dependency, concurrent treatment with nonspecific autophagy inhibitor chloroquine (CQ) ERK–MAPK inhibitors can synergistically block PDAC However, CQ limited in terms specificity potency. To find alternative anti-autophagy strategies, this study, we performed a CRISPR-Cas9...
<p>MEK inhibition synergizes with PIKfyvei to impair proliferation of PDAC cell lines</p>
<p>Identification of PIKfyve as a potential anti-autophagy target in PDAC</p>
<p>RAS ERK-MAPK pathway inhibition induces autophagic flux and synergizes with PIKfyvei to impair proliferation of PDAC cell lines</p>
<p>The PIKfyve inhibitor apilimod impairs autophagic flux in PDAC cells</p>
<p>Combined inhibition of PIKfyve and the RAS ERK-MAPK pathway induces apoptosis in PDAC cell lines</p>
<p>Combined inhibition of PIKfyve and RAS or MEK durably represses PDAC cell proliferation</p>
<p>Complete results of Apoptosis Array</p>
<p>PIKfyve inhibition results in the formation of LAMP-1 positive vacuoles</p>
<p>Chemically distinct PIKfyve inhibitors block proliferation and autophagy in PDAC cells</p>
<p>PIKfyve inhibition sensitizes PDAC organoids to RAS ERK-MAPK inhibition</p>
<p>The PIKfyve inhibitor apilimod impairs proliferation and blocks autophagy in PDAC cells</p>
Abstract Alteration of essential metabolic pathways is a major mechanism by which oncogenic KRAS promotes tumor development and growth in pancreatic ductal adenocarcinoma (PDAC). KRAS- driven PDAC dependent on nutrient scavenging pathways, including macropinocytosis autophagy to fuel the demand rapid proliferation. Thus, these processes are attractive targets for treatments PDAC. Acute loss results downregulation Additionally, our lab demonstrated that or inhibition ERK MAPK signaling...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. We previously determined that concurrent inhibition of autophagy, using the lysosomal inhibitor chloroquine (CQ), ERK, a small molecule ERK (ERKi), synergistically suppressed growth pancreatic cell lines patient xenograft-derived (PDX) organoids in vitro PDX tumors vivo. Our findings provided rationale for our initiation Phase I I/II clinical trials evaluating combination MEKi...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized clinically by poor survival and mechanistically KRAS- autophagy-dependent growth. We others previously demonstrated that inhibition of KRAS signaling via downstream the RAF-MEK-ERK pathway enhanced autophagic flux dependency PDAC on autophagy. Furthermore, we concurrent treatment with nonspecific autophagy inhibitor chloroquine (CQ) ERK MAPK inhibitors synergistically blocked These findings provided rationale for our...
Abstract Direct inhibitors of mutationally activated KRAS are currently under intense preclinical and clinical development, with one KRASG12C mutant-selective inhibitor approved. However, treatment-associated resistance to has been reported, ~60% relapsed patients acquiring mutations in signaling components both upstream downstream, at the level RAS itself, that led reactivation RAF-MEK-ERK PI3K-AKT effector pathways. Unexpectedly, we found ectopic expression constitutively MEK1, ERK1 or...