Abstract 2120: Platinum-based cancer chemotherapeutics inhibit STAT signaling by blocking the SH2 domain.

Abstract

Abstract Platinum-based drugs form the corner stone of many treatment schedules in cancer. Their main mechanism of actions is the covalent binding to DNA, leading to the formation of platinum-DNA adducts and thereby inducing apoptosis. Recently, other so called off-target effects of these drugs have been described. These include the induction of immunogenic cell death and the downregulation of inhibitory molecule Programmed Death-Ligand 2 by inactivation of signaling molecule/transcription factor STAT6, a member of the Signal Transducer and Activator of Transcription (STAT) protein family. STAT proteins play crucial roles in the pathogenesis and progression of cancer and much research is being conducted to identify inhibitors of STAT signaling for use in cancer treatment. Here, we investigated the potential of platinum-based chemotherapeutics to inhibit STAT signaling. We found that treatment of tumor cells of various origins with platinum drugs inhibit the activation of STAT proteins and leads to loss of cytokine-induced and constitutive STAT protein phosphorylation. Concurrently, a decrease of STAT protein nuclear accumulation was evident by confocal microscopy analysis. This resulted in a downregulation of STAT-regulated tumorigenic genes such as Bcl-xL, MCL-1, VEGF and survivin. Non-STAT target genes were not affected. Analysis of the known STAT inactivation pathways showed that these were not activated nor enhanced by treatment with platinum drugs. Finally, using a biochemical alphascreen-based assay, we demonstrated that platinum compounds directly interact with STAT proteins and inhibit binding to the SH2 domain. These findings provide novel insight into the mechanism of action of platinum drugs and show for the first time that these clinically used compounds directly affect important cellular signaling pathways. These results indicate that part of the efficacy of these drugs may be derived from their inhibition of STAT signaling and they provide important leads for the development of novel innovative treatment schedules in cancer that exploit the STAT-inhibiting effect of platinum drugs, for example by potentiating targeted therapies or immunotherapy. Citation Format: W. Joost Lesterhuis, Stanleyson V. Hato, Carl G. Figdor, Susumu Takahashi, Cornelis J.A. Punt, Akira Asai, I. Jolanda M. De Vries. Platinum-based cancer chemotherapeutics inhibit STAT signaling by blocking the SH2 domain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2013-2120