A5083411117- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Melanoma and MAPK Pathways
- Chromatin Remodeling and Cancer
- Computational Drug Discovery Methods
- Estrogen and related hormone effects
- Synthesis and biological activity
- Ubiquitin and proteasome pathways
- Vascular Malformations Diagnosis and Treatment
- Intracerebral and Subarachnoid Hemorrhage Research
- Multiple Myeloma Research and Treatments
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Intracranial Aneurysms: Treatment and Complications
- Click Chemistry and Applications
- HER2/EGFR in Cancer Research
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- MicroRNA in disease regulation
- Advanced Breast Cancer Therapies
- Protein Kinase Regulation and GTPase Signaling
- Cellular Mechanics and Interactions
- Advanced Biosensing Techniques and Applications
- Lung Cancer Treatments and Mutations
University of North Carolina at Chapel Hill
2012-2021
University of North Carolina Health Care
2018-2021
UNC Lineberger Comprehensive Cancer Center
2008-2020
Indiana University School of Medicine
2012-2017
Duke University Hospital
2002-2006
Duke University
2004-2006
Duke Medical Center
2002-2006
University of Colorado Boulder
1998
Therapeutics that target ERBB2, such as lapatinib, often provide initial clinical benefit, but resistance frequently develops. Adaptive responses leading to lapatinib involve reprogramming of the kinome through reactivation ERBB2/ERBB3 signaling and transcriptional upregulation activation multiple tyrosine kinases. The heterogeneity induced kinases prevents their targeting by a single kinase inhibitor, underscoring challenge predicting effective inhibitor combination therapies. We...
Cerebral cavernous malformations (CCMs) are sporadically acquired or inherited vascular lesions of the central nervous system consisting clusters dilated thin-walled blood vessels that predispose individuals to seizures and stroke. Familial CCM is caused by mutations in KRIT1 (CCM1) malcavernin (CCM2), murine ortholog which was concurrently characterized as osmosensing scaffold for MEKK3 (OSM). The roles proteins pathogenesis disorder remain largely unknown. Here, we use...
Mutations in KRIT1, a protein initially identified based on yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for development of inherited vascular disorder cerebral cavernous malformations (CCM1). As function KRIT1 and its role CCM pathogenesis remain unknown, we performed screens to identify additional binding partners. A fragment containing N-terminal 272 amino acid residues region lacking similarity any known upon database searches, was used as bait. From...
Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged clinical trial design. Despite responses specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib patients with triple-negative breast (TNBC) induced dramatic transcriptional responses, including upregulation receptor tyrosine kinases (RTK) comparing tumor samples before after one week treatment. In...
The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this a primary target for deregulated activation cancer. BRaf is activated by Ras proteins allowing oncogenes to constitutively activate pathway. Activating mutations are also frequent several cancers, being most common oncogenic mutation thyroid carcinoma and melanoma. There currently two inhibitors, vemurafenib dabrafenib, approved treatment malignant melanoma having activating mutations. Concurrent...
We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen genes within this 140-gene that promoted conversion of mesenchymal cell adhesion molecule-negative (EpCAM−) an EpCAM+/high phenotype. The 10 140 whose individual knockdown was sufficient promote EpCAM E-cadherin expression. Among these genes, RNAi silencing SWI/SNF...
The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 TS (TSKI4 cells) induces an intermediate state EMT, where retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation relationships among activity, EMT may reveal key regulators EMT. Here, we show that activity controls through ubiquitination degradation HDAC6. Loss TSKI4 results elevated HDAC6...
Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast cancer (TNBC). GSK2801, BAZ2A/B BDs, the imitation switch chromatin remodeling complexes, BRD9, SWI/SNF complex, demonstrated independent BRD4 control P-TEFb-mediated pause-release RNA polymerase II. GSK2801 or RNAi knockdown JQ1 selectively displaced BRD2...
RhoA and RhoC GTPases share 92% amino acid sequence identity, yet play different roles in regulating cell motility morphology. To understand these differences, we developed validated a biosensor of activation (RhoC FLARE). This was used together with to compare the spatio-temporal dynamics activity during protrusion/retraction macropinocytosis. Both were activated similarly at edge, but regions more distal from edge showed higher protrusion. The two isoforms differed markedly kinetics...
MEK1/2 inhibitors such as AZD6244 are in clinical trials for the treatment of multiple cancers, including breast cancer. Targeted kinase inhibition can induce compensatory kinome changes, rendering single therapeutic agents ineffective. To identify target proteins to be used a combinatorial approach inhibit tumor cell growth, we novel strategy that identified microRNAs (miRNAs) synergized with viability claudin-low cancer line MDA-MB-231. Screening miRNA mimic library revealed ability...
Most novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors associated with cardiotoxicity, whereas others appear be cardiosafe. The basis for this distinction is unclear, as the molecular effects in heart.
Multiplexed small molecule inhibitors covalently bound to Sepharose beads (MIBs) were used capture functional kinases in luminal, HER2-enriched and triple negative (basal-like claudin-low) breast cancer cell lines tumors. Kinase MIB-binding profiles at baseline without perturbation proteomically distinguished the four subtypes. Understudied kinases, whose disease associations pharmacology are generally unexplored, highly represented taxonomies integrated into signaling subnetworks with that...
Abstract Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but significant fraction (HER2+) cancers recur or fail respond. Anti-HER2 monoclonal antibodies, like trastuzumab pertuzumab, and ATP active site inhibitors lapatinib, commonly lack durability because adaptive changes in tumor leading resistance. HER2+ cell line responses inhibition with lapatinib were analyzed by RNAseq ChIPseq characterize transcriptional...
Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors conventional have limited efficacy. Various model systems been created several targets implicated in NF2-driven tumorigenesis based on known effects of the absence merlin, product NF2 gene. We tested priority compounds biology traditional dose-concentration studies meningioma schwann cell systems. Concurrently,...
A live-cell analysis platform measures growth rate and phenotypic properties of up to 100,000 clones per experiment.
ABSTRACT Discovering transcriptional variation in the absence of underlying genomic contributions hinders understanding molecular mechanisms disease. To assess this coordination individual cells, we leveraged a new workflow, ResolveOME, exploiting attributes primary template-directed amplification (PTA) to enable accurate, complete-genome assessment single-nucleotide conjunction with full-transcript RNA-seq. In cultured AML cells resistant FLT3 inhibitor quizartinib, uncovered missense...