A5005237041- Pancreatic and Hepatic Oncology Research
- Advanced Breast Cancer Therapies
- Colorectal Cancer Treatments and Studies
- Hippo pathway signaling and YAP/TAZ
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Growth Hormone and Insulin-like Growth Factors
- Neuroendocrine Tumor Research Advances
- Cancer Research and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Melanoma and MAPK Pathways
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Biochemical and Molecular Research
- Epigenetics and DNA Methylation
- Cancer Mechanisms and Therapy
- Plant Surface Properties and Treatments
- Amino Acid Enzymes and Metabolism
- Pancreatic function and diabetes
- RNA modifications and cancer
- ATP Synthase and ATPases Research
- Protein Degradation and Inhibitors
- Endoplasmic Reticulum Stress and Disease
- Histone Deacetylase Inhibitors Research
University of North Carolina at Chapel Hill
2019-2025
UNC Lineberger Comprehensive Cancer Center
2019-2024
Segeberger Kliniken
2024
Cornell University
2013-2020
Ithaca College
2013-2015
Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation KRAS in promoting the development and malignant growth pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration p16INK4A with inhibitors CDK4 CDK6 (CDK4/6) has shown limited clinical efficacy PDAC. Here, we found concurrent treatment both CDK4/6 inhibitor (CDK4/6i) an ERK-MAPK (ERKi) synergistically suppresses PDAC cell lines organoids by cooperatively...
Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by mutations 1,2 . RMC-7977 is highly selective inhibitor active GTP-bound forms KRAS, HRAS and NRAS, affinity for both mutant wild-type variants 3 More than 90% cases pancreatic ductal adenocarcinoma (PDAC) activating in KRAS 4 Here we assessed therapeutic comprehensive range PDAC models. We observed broad pronounced anti-tumour activity across models...
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...
The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, NAD+-dependent lysine deacylase, plays key role in stabilizing GLS. In transformed cells, SIRT5 regulates metabolism by desuccinylating thereby protecting it from ubiquitin-mediated...
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...
Significance The work described here was motivated by our previous discovery of a connection between Rho GTPase activation and the up-regulation mitochondrial glutaminase C (GAC), which is responsible for satisfying glutamine addiction cancer cells. This originally established identification lead compound, 968, new class inhibitors oncogenic transformation. Although GAC identified as putative target how it regulated poorly understood. Here we provide important insights into actions through...
Altered glycolytic flux in cancer cells (the "Warburg effect") causes their proliferation to rely upon elevated glutamine metabolism ("glutamine addiction"). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes first step and therefore represents a potential therapeutic target. The small molecule CB-839 was reported be more potent than other allosteric GAC inhibitors, including parent compound bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl (BPTES),...
Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development improved therapies. As KRAS mutations are found in 95% PDAC and critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. macrometabolic process autophagy is upregulated KRAS-mutant PDAC, growth reliant on autophagy. However, inhibition as monotherapy using lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy....
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...
Highlights•p130Cas and βIII-tubulin support PDAC growth by enhancing MYC expression•p130Cas transcriptionally regulates through SRC-p130Cas-DOCK1-RAC1-β-catenin•Microtubules post-translationally regulate stability calpains•Triple targeting of ERK/p130Cas/tubulin with ERKi KX2-391 inhibits growthSummaryTo identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen determine that suppression BCAR1 sensitizes cancer cells to...
The first step in glutamine catabolism is catalysis by the mitochondrial enzyme glutaminase, with a specific isoform, glutaminase C (GAC), being highly expressed cancer cells. GAC activation requires formation of homotetramers, promoted anionic allosteric activators such as inorganic phosphate. This leads to proper orientation flexible loop proximal dimer-dimer interface that essential for (i.e. "activation loop"). A major class inhibitors GAC, prototype...
Abstract KRAS is mutationally activated in 95% of pancreatic ductal adenocarcinoma (PDAC) patients. Direct inhibitors are under intense preclinical and clinical development, with two KRASG12C mutant-selective (G12Ci) now approved. However, treatment-associated resistance to has been reported the clinic highlighting an urgent need identify both additional therapeutic targets novel combination treatment strategies inhibitors. To that end, we performed a CRISPR/Cas9 loss-of-function screen...
The ability of a cell to exhibit anchorage independent growth is hallmark cancer, and has been extensively investigated in hopes finding new therapeutic strategies. In particular, the processes that give rise support this dysregulated phenotype, which allows cells proliferate absence survival signals resulting from their attachment basement membrane, interest. contribution oncogenes tumor suppressors on well studied; however, alterations cellular metabolism process are much less defined....
We and others have recently shown that proteins involved in the DNA damage response (DDR) are critical for KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell growth vitro.However, CRISPR-Cas9 library enabled us to identify these key had limited representation of DDR-related genes.To further investigate DDR this context, we performed a comprehensive, DDRfocused loss-of-function screen.This screen identified valosin-containing protein (VCP) as an essential gene PDAC lines.We observed...