Michael Kastan

Positions:

William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Director of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

Washington University in St. Louis

Ph.D. 1984

Washington University in St. Louis

Grants:

Using bacterial CRISPR/Cas endonucleases to selectively eliminate HPV-transformed cells in vivo

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Development and Validation of Novel Therapeutic Targets in Anal Cancer

Administered By
Medicine, Medical Oncology
Role
Collaborator
Start Date
End Date

The role of ATM in Metabolic Stress Responses

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

The role of ATM in Metabolic Stress Responses

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

Metabolic Sensing and Stress Response Deficit in Ataxia Telangiectasia

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
End Date

Publications:

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in childhood and early adulthood. An adolescent girl with minimal neurological symptoms was diagnosed with A-T 8 years after completing therapy for T-cell acute lymphoblastic leukemia, following a diagnosis of ATM-mutated breast cancer in her mother. We highlight the importance of recognizing ATM mutations in T-cell acute lymphoblastic leukemia, appreciating the phenotypic heterogeneity of A-T, and defining optimal cancer screening in A-T patients.
Authors
Sze, S-GK; Lederman, HM; Crawford, TO; Wangler, MF; Lewis, AM; Kastan, MB; Dibra, HK; Taylor, AMR; Wechsler, DS
MLA Citation
Sze, Sei-Gyung K., et al. “Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.J Pediatr Hematol Oncol, Nov. 2019. Pubmed, doi:10.1097/MPH.0000000000001672.
URI
https://scholars.duke.edu/individual/pub1421634
PMID
31743320
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Published Date
DOI
10.1097/MPH.0000000000001672

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

Background:Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods:Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results:For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions:These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.
Authors
McGill, JB; Johnson, M; Hurst, S; Cade, WT; Yarasheski, KE; Ostlund, RE; Schechtman, KB; Razani, B; Kastan, MB; McClain, DA; de Las Fuentes, L; Davila-Roman, VG; Ory, DS; Wickline, SA; Semenkovich, CF
MLA Citation
McGill, Janet B., et al. “Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.Diabetology & Metabolic Syndrome, vol. 11, Jan. 2019, p. 61. Epmc, doi:10.1186/s13098-019-0456-4.
URI
https://scholars.duke.edu/individual/pub1404051
PMID
31384309
Source
epmc
Published In
Diabetol Metab Syndr
Volume
11
Published Date
Start Page
61
DOI
10.1186/s13098-019-0456-4

ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome.

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.
Authors
Schneider, JG; Finck, BN; Ren, J; Standley, KN; Takagi, M; Maclean, KH; Bernal-Mizrachi, C; Muslin, AJ; Kastan, MB; Semenkovich, CF
MLA Citation
Schneider, Jochen G., et al. “ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome.Cell Metab, vol. 4, no. 5, Nov. 2006, pp. 377–89. Pubmed, doi:10.1016/j.cmet.2006.10.002.
URI
https://scholars.duke.edu/individual/pub779343
PMID
17084711
Source
pubmed
Published In
Cell Metabolism
Volume
4
Published Date
Start Page
377
End Page
389
DOI
10.1016/j.cmet.2006.10.002

The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response.

The telomeric protein TRF2 is required to prevent mammalian telomeres from activating DNA damage checkpoints. Here we show that overexpression of TRF2 affects the response of the ATM kinase to DNA damage. Overexpression of TRF2 abrogated the cell cycle arrest after ionizing radiation and diminished several other readouts of the DNA damage response, including phosphorylation of Nbs1, induction of p53, and upregulation of p53 targets. TRF2 inhibited autophosphorylation of ATM on S1981, an early step in the activation of this kinase. A region of ATM containing S1981 was found to directly interact with TRF2 in vitro, and ATM immunoprecipitates contained TRF2. We propose that TRF2 has the ability to inhibit ATM activation at telomeres. Because TRF2 is abundant at chromosome ends but not elsewhere in the nucleus, this mechanism of checkpoint control could specifically block a DNA damage response at telomeres without affecting the surveillance of chromosome internal damage.
Authors
Karlseder, J; Hoke, K; Mirzoeva, OK; Bakkenist, C; Kastan, MB; Petrini, JHJ; de Lange, T
MLA Citation
Karlseder, Jan, et al. “The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response.Plos Biol, vol. 2, no. 8, Aug. 2004, p. E240. Pubmed, doi:10.1371/journal.pbio.0020240.
URI
https://scholars.duke.edu/individual/pub779355
PMID
15314656
Source
pubmed
Published In
Plos Biology
Volume
2
Published Date
Start Page
E240
DOI
10.1371/journal.pbio.0020240

Interaction of FANCD2 and NBS1 in the DNA damage response.

Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) are autosomal recessive chromosome instability syndromes with distinct clinical phenotypes. Cells from individuals affected with FA are hypersensitive to mitomycin C (MMC), and cells from those with NBS are hypersensitive to ionizing radiation. Here we report that both NBS cell lines and individuals with NBS are hypersensitive to MMC, indicating that there may be functional linkage between FA and NBS. In wild-type cells, MMC activates the colocalization of the FA subtype D2 protein (FANCD2) and NBS1 protein in subnuclear foci. Ionizing radiation activates the ataxia telangiectasia kinase (ATM)-dependent and NBS1-dependent phosphorylation of FANCD2, resulting in an S-phase checkpoint. NBS1 and FANCD2 therefore cooperate in two distinct cellular functions, one involved in the DNA crosslink response and one involved in the S-phase checkpoint response.
Authors
Nakanishi, K; Taniguchi, T; Ranganathan, V; New, HV; Moreau, LA; Stotsky, M; Mathew, CG; Kastan, MB; Weaver, DT; D'Andrea, AD
MLA Citation
Nakanishi, Koji, et al. “Interaction of FANCD2 and NBS1 in the DNA damage response.Nat Cell Biol, vol. 4, no. 12, Dec. 2002, pp. 913–20. Pubmed, doi:10.1038/ncb879.
URI
https://scholars.duke.edu/individual/pub779369
PMID
12447395
Source
pubmed
Published In
Nature Cell Biology
Volume
4
Published Date
Start Page
913
End Page
920
DOI
10.1038/ncb879