MAPKAP Kinase-2 as A Specific Target for Blocking Proliferation of P53-Defective Cells

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 Representation of a unified model of the kinase-dependent DNA damage checkpoint. In this model, parallel pathways in the DNA damage checkpoint signal transduction network converge on common substrates by signaling to downstream kinases with similar phosphorylation motif specificities. φ indicates hydrophobic residues. The dashed line from Chk1 to Cdc25B/C indicates that this phosphorylation event remains controversial in response to ionizing radiation.MAPKAP kinase-2 depletion sensitizes U2OS cells to the antiproliferative effects of cisplatin and doxorubicin. Luciferase shRNA- or MAPKAP Kinase 2 shRNA-expressing U2OS cells were mock treated or treated for eight hours with increasing doses of cisplatin (A) or doxorubicin (B) in a clonogenic survival assay. Cells were washed, trypsinized, and replated at a density of 5000 cells/10 cm2 dish. Eight days later, colonies were visualized using Crystal Violet staining and counted. Insets show magnified views. (C) and (D) are graphs showing the quantitation of the results shown in (A) and (B). Assays were performed in triplicate for each condition and normalized to mock treated cells.MAPKAP kinase-2 depletion suppresses tumor formation in vivo after implantation of chemotherapy-treated cancer cells. H-Ras-V12 transformed p53−/− MEFs were transfected with siRNA oligonucleotides against GFP or MAPKAP kinase-2. Forty-eight hours following transfection, cells were treated for eight hours with either cisplatin (1 μm), doxorubicin (0.1 μm), or vehicle alone. Two individual injections of 106 cells each were performed into the subcutaneous tissues of each flank of NCR nude outbred mice. (A) is a dorsal view of the resulting tumors fifteen days after each of the indicated treatments. Control siRNA-transfected cells are in the right flank and MAPKAP kinase-2 siRNA-treated cells are in the left flank. (B) is a close-up view of the resulting tumors that formed in the absence of DNA damaging chemotherapy pre-treatment. In (C), the efficiency of siRNA-mediated knockdown on murine MAPKAP kinase-2 was assessed by immunoblotting lysates from the MEFs prior to tumor implantation. (D) is a graph showing an analysis of tumor weight at the fifteen-day endpoint.
Categories
Inventors
Professor Michael Yaffe
Department of Biology, MIT
External Link (yaffelab.mit.edu)
Isaac Manke
Department of Biology, MIT
Hans Reinhardt
Koch Institute for Integrative Cancer Research
Managed By
Jon Gilbert
MIT Technology Licensing Officer
Patent Protection

Mapkap kinase-2 as a specific target for blocking proliferation of P53-defective cells

US Patent 8,440,610

Mapkap Kinase-2 as a Specific Target for Blocking Proliferation of P53-Defective Cells

US Patent 2014-0037755
Publications
p53-Deficient Cells Rely on ATM- and ATR-Mediated Checkpoint Signaling through the p38MAPK/MK2 Pathway for Survival after DNA Damage
Cancer Cell, February 13 2007, P. 175–189
A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo
Cell Reports, November 27 2013, P. 868–877

Applications

This invention may be used for the treatment of cellular proliferative disorders including cancer.

Problem Addressed

Improved cancer treatments are desperately needed for clinical use. Unfortunately, the complex signaling network that preserves genomic integrity, activated in response to DNA damage, is not fully understood. Cells either arrest the cell cycle to preform DNA repair or, instead, undergo apoptosis if DNA damage is great. This invention is a method of treating p53 deficient tumors.

Technology

MAPKAP Kinase-2 (MK2) is critical for the activation of G1, S-phase and G2/M checkpoints after exposure to chemotherapeutic agents. Inhibition of MAPKAP Kinase-2 significantly increases the anti-proliferative and cytotoxic effects of cisplatin and doxorubucin on p53 deficient tumor cells. p53 is a tumor suppressor that arrests a cell in G1 or leads to apoptosis. Most tumors have a disrupted p53 pathway allowing MAPKAP Kinase-2 inhibition to selectively target malignancies without affecting normal, healthy cells. This invention includes discovered MAPKAP kinase-2 inhibitors, pharmaceutical compounds containing such inhibitors, and screening methods for identifying additional inhibitors.

Advantages

  • Broad tumor-specific chemosensitization therapy 
  • Healthy cells are unaffected by treatment