Poster Presentation 28th Lorne Cancer Conference 2016

Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity (#181)

Stanleyson V Hato 1 , Carl G Figdor 1 , Susumu Takahashi 2 , Altuna Halilovic 1 , Anja E Pen 1 , Kalijn F Bol 1 , Johan H van Krieken 1 , Carla M Van Herpen 1 , Cornelis J Punt , Akira Asai 2 , Jolanda M De Vries 1 , Willem J Lesterhuis 3
  1. Department of Tumor Immunology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
  2. Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, , Shizuoka, Japan
  3. University of Western Australia, Nedlands, WA, Australia

Background

Platinum-based chemotherapeutics are amongst the most powerful and most widely used anti-cancer drugs. Although their exact mechanism of action is not well understood, it is generally thought to be mediated through covalent DNA binding. Here, we investigated the effect of platinum-based chemotherapeutics on signaling through signal transducer and activator of transcription (STAT) proteins, which are involved in many oncogenic signaling pathways and are often upregulated in cancer.

Results

We found that at clinically relevant concentrations, all platinum compounds strongly inhibit STAT phosphorylation, resulting in loss of constitutively activated STAT proteins in multiple distinct cancer cell lines in vitro. We demonstrate that this platinum-induced STAT inactivation leads to loss of STAT dimerization, reduced translocation of STAT proteins from the cytoplasm to the nucleus and subsequent downregulation of downstream cytokine-, pro-survival- and anti-apoptotic- target genes in cancer cells. Using a cell-free alpha screen assay, we demonstrate that platinum drugs directly bind to STAT proteins and specifically inhibit phospho-tyrosine binding to SH2 domains. Importantly, we found that active tumor STAT3 as assessed by immunohistochemistry directly correlates with response to cisplatin in a cohort of 96 head and neck squamous cell cancer patients, treated with either cisplatin plus radiotherapy or radiotherapy alone. STAT3 may therefore serve as a predictive biomarker that can be used to choose whether a patient is likely or not to benefit from platinum-based therapy.

Conclusions

Our data provide mechanistic insight into a novel, non-DNA-targeted mechanism of action of platinum cancer chemotherapeutics. These results may lead to the development of novel treatment schedules, exploiting this STAT modulating effect to potentiate other therapeutic strategies such as immunotherapy or oncogene-targeted therapy. Potentially, pretreatment STAT analysis provides a first possibility to personalize cytotoxic chemotherapy treatment in cancer.