Anette Duensing, M.D.
Assistant Professor
M.D., Hannover Medical School
Hannover, Germany, 1997
Email: aduensin@pitt.edu
Lab Website: http://labs.mgb.pitt.edu/duensing/index.htm
Research Interest:
The Duensing laboratory is interested in the molecular circuitry of gastrointestinal stromal tumors (GISTs) and their response to targeted therapies.
Gastrointestinal stromal tumors are caused by a single oncogenic mutation in either the KIT or PDGFRA kinase genes leading to constitutive activation of the respective receptor tyrosine kinase protein. They are therefore the prototypical example of a solid tumor entity that can be successfully treated with a novel class of drugs, small molecule protein kinase inhibitors. Imatinib mesylate (Gleevec™) is the first and most prominent compound that belongs to this group.
Although it is know that imatinib rapidly shuts down aberrant KIT and PDGFRA signaling activity, the precise molecular events that lead to GIST cell apoptosis are not well understood. Our lab is interested in elucidating these mechanisms to generate novel treatment options that are more effective and do not lead to therapy resistance. Moreover, understanding the mode of action of imatinib will be instrumental to develop novel small molecule protein kinase inhibitors and to identify other proteins that can be targeted therapeutically - in GISTs and in other malignancies.
Our previous work established that histone H2AX, a protein that is well characterized for its function in DNA damage signaling, has a pivotal role in imatinib-induced apoptosis in GIST. We are currently studying the pro-apoptotic function of histone H2AX in more detail and are investigating the deregulation of DNA damage signaling in GISTs before and after imatinib therapy. These experiments are complemented by efforts to identify pathways leading to cell cycle arrest in imatinib-treated GIST cells. It has been observed clinically and experimentally that not all GIST cells that are treated with imatinib undergo apoptosis but rather seem to be dormant. We have shown that imatinib directly leads to an exit of the cell division cycle in GIST and are currently following up on this finding. A third line of interest focuses on a more general search for KIT/PDGFRA downstream kinases that are involved in the regulation of apoptosis and tumor cell quiescence. To that end, we are using medium- to large-scale siRNA library screens.
Our ultimate goal is to understand the molecular biology of GISTs and other malignancies that are driven by oncogenically activated kinases. With this framework we hope to translate our research into the development of innovative treatment strategies to ultimately improve the therapeutic options for all cancer patients.
Representative Publication
Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S, Demetri GD, Fletcher CDM, Fletcher JA. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 2004; 23:3999-4006.
Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, Fletcher JA, Fletcher CDM. KIT-negative gastrointestinal stromal tumors: Proof of concept and therapeutic implications. Am. J. Surg. Pathol. 2004; 28:889-894.
Duensing A, Joseph NE, Medeiros F, Smith F, Hornick JL, Heinrich MC, Corless CL, Demetri GD, Fletcher CDM, Fletcher JA. Protein Kinase C theta (PKC ) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Res. 2004; 64:5127-5131.
Li FP, Fletcher JA, Heinrich MC, Garber JE, Sallan SE, Curiel-Lewandrowski C, Duensing A, van de Rijn M, Schnipper LE, Demetri GD. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J. Clin. Oncol. 2005; 23:2735-2743.
Liu Y, Tseng M, Perdreau SA, Rossi F, Antonescu C, Besmer P, Fletcher JA, Duensing S, Duensing A. Histone H2AX is a mediator of gastrointestinal stromal tumor (GIST) cell apoptosis following treatment with imatinib mesylate. Cancer Res. 2007; 67:2685-2692.
Bauer S, Duensing A, Demetri GD, Fletcher JA. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-Kinase/AKT is a crucial survival pathway. Oncogene 2007; 26:7552-7559.
Liu Y, Parry JA, Chin A, Duensing S, Duensing A. Soluble histone H2AX is induced by DNA replication stress and sensitizes cells to undergo apoptosis. Mol. Cancer 2008; 7:61.
Liu Y, Perdreau SA, Chatterjee P, Wan L, Kuan, SF, Duensing A. Imatinib mesylate induces quiescence in gastrointestinal stromal tumor (GIST) cells through the CDH1-SKP2-p27Kip1 signaling axis. Cancer Res. 2008, 68:9015-23.
