Donald McDonnell

Overview:

The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.

Positions:

Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, in the School of Medicine

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor in Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1988

Baylor College of Medicine

Grants:

The Role of Epigenetic Plasticity in Breast Cancer Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Targeting precursor neural (N)-cadherin to eliminate chemotherapy-resistant triple-negative breast tumor cells

Awarded By
Department of Defense
Role
Co Investigator
Start Date
End Date

A Novel Function for ALK4 in Suppressing Breast Cancer Progression

Administered By
Medicine, Medical Oncology
Awarded By
Susan G. Komen Breast Cancer Foundation
Role
Co-Mentor
Start Date
End Date

Nonclassical signaling of the androgen receptor polyproline domain

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

G Protein Involvement in Oncogenesis and Metastasis

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date

Publications:

ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.
Authors
Mayro, B; Hoj, JP; Cerda-Smith, CG; Hutchinson, HM; Caminear, MW; Thrash, HL; Winter, PS; Wardell, SE; McDonnell, DP; Wu, C; Wood, KC; Pendergast, AM
MLA Citation
Mayro, Benjamin, et al. “ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.Proc Natl Acad Sci U S A, vol. 120, no. 16, Apr. 2023, p. e2210418120. Pubmed, doi:10.1073/pnas.2210418120.
URI
https://scholars.duke.edu/individual/pub1571506
PMID
37040401
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
120
Published Date
Start Page
e2210418120
DOI
10.1073/pnas.2210418120

SGC-CAMKK2-1: A Chemical Probe for CAMKK2.

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.
Authors
Wells, C; Liang, Y; Pulliam, TL; Lin, C; Awad, D; Eduful, B; O'Byrne, S; Hossain, MA; Catta-Preta, CMC; Ramos, PZ; Gileadi, O; Gileadi, C; Couñago, RM; Stork, B; Langendorf, CG; Nay, K; Oakhill, JS; Mukherjee, D; Racioppi, L; Means, AR; York, B; McDonnell, DP; Scott, JW; Frigo, DE; Drewry, DH
MLA Citation
Wells, Carrow, et al. “SGC-CAMKK2-1: A Chemical Probe for CAMKK2.Cells, vol. 12, no. 2, Jan. 2023. Pubmed, doi:10.3390/cells12020287.
URI
https://scholars.duke.edu/individual/pub1563637
PMID
36672221
Source
pubmed
Published In
Cells
Volume
12
Published Date
DOI
10.3390/cells12020287

Molecular Pharmacology of Estrogen and Progesterone Receptors

This chapter provides an update on the mechanisms of action of estrogen and progesterone. Particularly important concepts include nongenomic effects, receptor isoforms that affect agonist/antagonist actions, and the role of coactivators and corepressors in various tissues. The steroid hormones estrogen and progesterone are low-molecular weight, lipophilic hormones that through their action as modulators of distinct signal transduction pathways, are involved in the regulation of reproductive function. These hormones are also important regulators in bone, the cardiovascular system, and the central nervous system. Despite their different roles in these systems, it has become apparent that estrogens and progestins are mechanistically similar. Insights gleaned from the study of each hormone have advanced the understanding of this class of molecules as a whole. Some of the recent mechanistic discoveries that have occurred in the field are highlighted and the subsequent changes in our understanding of the pharmacology of this class of steroid hormones are explored.
Authors
Sherk, AB; McDonnell, DP
MLA Citation
Sherk, A. B., and D. P. McDonnell. “Molecular Pharmacology of Estrogen and Progesterone Receptors.” Treatment of the Postmenopausal Woman: Basic and Clinical Aspects, Third Edition, 2007, pp. 17–28. Scopus, doi:10.1016/B978-012369443-0/50004-1.
URI
https://scholars.duke.edu/individual/pub1567819
Source
scopus
Published Date
Start Page
17
End Page
28
DOI
10.1016/B978-012369443-0/50004-1

Estrogens regulate tumor associated tissue eosinophilia to promote tumor growth

Authors
Artham, S; Goyal, A; Byemerwa, J; Chang, C-Y; Mcdonnell, DP
MLA Citation
Artham, Sandeep, et al. “Estrogens regulate tumor associated tissue eosinophilia to promote tumor growth.” Cancer Immunology Research, vol. 10, no. 12, 2022.
URI
https://scholars.duke.edu/individual/pub1564947
Source
wos-lite
Published In
Cancer Immunology Research
Volume
10
Published Date

Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) cells but is upregulated in tumor-infiltrating NK cells where it suppresses apoptosis and promotes proliferation. NK cell-intrinsic deletion of CaMKK2 increased metastatic progression in several murine models, establishing a critical role for this enzyme in NK cell-mediated antitumor immunity. Ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK-cell survival. These results indicate an important scaffolding function for CaMKK2 in NK cells and suggest that competitive CaMKK2 inhibitors and ligand-directed degraders (LDD) are likely to have distinct therapeutic utilities. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactic acid-rich tumor microenvironment. The findings of this study should inform strategies to manipulate the CaMKK2-signaling axis as a therapeutic approach in cancer.
Authors
Juras, PK; Racioppi, L; Mukherjee, D; Artham, S; Gao, X; Akullian D'Agostino, L; Chang, C-Y; McDonnell, DP
MLA Citation
Juras, Patrick K., et al. “Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.Cancer Immunol Res, vol. 11, no. 1, Jan. 2023, pp. 109–22. Pubmed, doi:10.1158/2326-6066.CIR-22-0391.
URI
https://scholars.duke.edu/individual/pub1555416
PMID
36301267
Source
pubmed
Published In
Cancer Immunol Res
Volume
11
Published Date
Start Page
109
End Page
122
DOI
10.1158/2326-6066.CIR-22-0391

Research Areas:

3T3 Cells
8-Bromo Cyclic Adenosine Monophosphate
ADP-ribosyl Cyclase 1
Acetates
Acetyl Coenzyme A
Acetyltransferases
Adolescent
Adult
Age Factors
Aging
Aldehyde Dehydrogenase
Allosteric Regulation
Amino Acid Motifs
Amino Acid Sequence
Androgen Receptor Antagonists
Androgens
Antigens, CD
Antigens, CD38
Antigens, Nuclear
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Apoptosis
Aromatase
Aryl Hydrocarbon Receptor Nuclear Translocator
Atlases as Topic
Autocrine Communication
Benzhydryl Compounds
Benzoates
Binding Sites
Biological Transport
Biomimetic Materials
Blotting, Western
Bone and Bones
Breast
Breast Neoplasms
Bruch Membrane
COS Cells
Cadherins
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Carcinoma, Hepatocellular
Cardiovascular System
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Cercopithecus aethiops
Chemokine CXCL12
Child
Cholestanetriol 26-Monooxygenase
Cholesterol
Cholesterol Side-Chain Cleavage Enzyme
Chromans
Chromatin
Chromatin Immunoprecipitation
Chrysenes
Cinnamates
Cluster Analysis
Combinatorial Chemistry Techniques
Consensus Sequence
Cytoprotection
DNA Primers
DNA-Binding Proteins
Dehydroepiandrosterone
Dieldrin
Diethylstilbestrol
Dose-Response Relationship, Drug
Down-Regulation
Drug Design
Drug Discovery
Drug Evaluation, Preclinical
Drug Interactions
Drug Partial Agonism
Drug Resistance
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Drug Synergism
E2F1 Transcription Factor
Enhancer Elements, Genetic
Enzyme Activation
Enzyme Inhibitors
Enzyme-Linked Immunosorbent Assay
Estradiol
Estradiol Antagonists
Estradiol Congeners
Estrenes
Estriol
Estrogen Antagonists
Estrogen Receptor Modulators
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogen Replacement Therapy
Estrogens
Estrogens, Non-Steroidal
Estrone
Extracellular Matrix
Female
Flow Cytometry
Furylfuramide
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Gene Library
Genes, Reporter
Glucose
Glucose Transporter Type 1
Gonadal Steroid Hormones
Green Fluorescent Proteins
HCT116 Cells
HEK293 Cells
Haplorhini
HeLa Cells
Heat-Shock Proteins
Hematopoiesis
Hepatocyte Nuclear Factor 4
Hexokinase
Histone Acetyltransferases
Histone Deacetylase Inhibitors
Homeodomain Proteins
Hormone Antagonists
Humans
Hydroxycholesterols
Hydroxymethylglutaryl-CoA Synthase
Immunoblotting
Immunohistochemistry
Immunosuppressive Agents
Indoles
Induced Pluripotent Stem Cells
Inflammatory Breast Neoplasms
Insecticides
Insulin-Like Growth Factor I
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Kruppel-Like Transcription Factors
Leupeptins
Ligands
Lipofuscin
Lipoproteins, LDL
Locus Coeruleus
MCF-7 Cells
MSX1 Transcription Factor
Macrophages
Macular Degeneration
Male
Mammary Glands, Human
Metribolone
Mice
Mice, Congenic
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, Nude
Mice, SCID
Mice, Transgenic
Microscopy, Electron
Middle Aged
Mifepristone
Mitochondria
Mitogen-Activated Protein Kinases
Molecular Conformation
Molecular Sequence Data
Molecular Targeted Therapy
Multiple Myeloma
Mutagenesis, Site-Directed
NF-kappa B
Norepinephrine
Nuclear Receptor Co-Repressor 1
Nuclear Receptor Co-Repressor 2
Nuclear Receptor Coactivator 1
Nuclear Receptor Coactivator 2
Nuclear Receptor Coactivators
Organ Size
Orphan Nuclear Receptors
Osteoblasts
Osteoclasts
Osteogenesis
Osteoporosis
Ovariectomy
Oxidation-Reduction
PPAR gamma
Peptide Library
Peroxidase
Peroxisome Proliferator-Activated Receptors
Phenols
Pigment Epithelium of Eye
Plicamycin
Polymerase Chain Reaction
Progesterone
Progestins
Promegestone
Promoter Regions, Genetic
Prostate-Specific Antigen
Prostatic Neoplasms
Protein Conformation
Protein Kinase Inhibitors
Protein Kinases
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases
Proteins
Proteolysis
RNA Interference
RNA, Messenger
RNA, Small Interfering
RNA-Binding Proteins
Raloxifene
Raloxifene Hydrochloride
Rats
Rats, Sprague-Dawley
Rats, Wistar
Reactive Oxygen Species
Receptor Cross-Talk
Receptor, IGF Type 1
Receptor, erbB-2
Receptors, Androgen
Receptors, Aryl Hydrocarbon
Receptors, CXCR4
Receptors, Calcitriol
Receptors, Cytoplasmic and Nuclear
Receptors, Estrogen
Receptors, Glucocorticoid
Receptors, Progesterone
Receptors, Retinoic Acid
Receptors, Steroid
Recombinant Fusion Proteins
Recombinant Proteins
Repetitive Sequences, Nucleic Acid
Repressor Proteins
Response Elements
Retinal Dehydrogenase
Retinal Pigment Epithelium
Retinoblastoma Protein
Retinoid X Receptor alpha
Retinoid X Receptors
Retinoids
Reverse Transcriptase Polymerase Chain Reaction
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Selective Estrogen Receptor Modulators
Sequence Deletion
Species Specificity
Stem Cell Transplantation
Steroid 17-alpha-Hydroxylase
Steroid Hydroxylases
Steroids
Stilbenes
Structure-Activity Relationship
T-Lymphocytes
Tacrolimus Binding Proteins
Tamoxifen
Thiazolidinediones
Tight Junctions
Toxaphene
Trans-Activators
Transcription Factor AP-1
Transcription Factors
Transcription, Genetic
Transcriptional Activation
Transfection
Translocation, Genetic
Tretinoin
Tumor Burden
Two-Hybrid System Techniques
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases
Up-Regulation
Uterus
Vascular Endothelial Growth Factor A
Wnt Proteins
Young Adult
beta Catenin