Abstract 3794: Sorafenib suppresses desmoid tumor growth and invasion via inhibition of ERK signaling
Authors: Laura M. Rosenberg, Monica M. Bertagnolli, Nancy L. Cho
Journal: Cancer Research (2014)

Abstract Introduction: Desmoid tumors (DTs) are mesenchymal tumors that occur sporadically or in association with familial adenomatous polyposis (FAP). Surgical resection is the initial treatment of choice for DTs, but medical options are limited for patients with recurrent or unresectable disease. Sorafenib is a multikinase inhibitor that blocks cell proliferation in various cancers via suppression of the Raf/MEK/ERK signaling cascade. The PI3K-Akt-mTOR pathway is also known to be a key regulator of cell proliferation involved in carcinogenesis. Sorafenib activity against desmoid tumor cells has not yet been well characterized. Here, we examined the effects of sorafenib on patient-derived DT cell lines, with the aim of characterizing the efficacy and mechanism of action of sorafenib in DTs. Methods: DT-derived cells were isolated and cultured from fresh patient tumor specimens, resulting in 12 distinct cell lines, from both sporadic and FAP patients. Human dermal fibroblasts (HDF) were purchased from ATCC for use as controls. Early passage cells were treated with increasing doses of sorafenib, and the effect at 72 hours was measured by CellTiter proliferation assay. To assess invasion, DT cells and HDF were plated in invasion chambers with either 5 µM sorafenib or vehicle, with resultant invasive cells counted after 24 hours. Cells were treated with 5 µM sorafenib, and lysates were collected at intervals from 15 minutes to 3 days. These lysates were used for immunoblot analysis, as well as phosphoprotein signaling arrays. Results: Sorafenib at 10 µM significantly inhibited DT-derived cell proliferation, suppressing growth in each of 3 sporadic and 3 FAP cell lines to less than 25% relative to controls, while the same concentration minimally affected HDF growth. In addition, sorafenib inhibited the invasiveness of DT-derived cells in comparison to controls. Immunoblot analysis revealed that sorafenib inhibited ERK phosphorylation, and this effect correlated with inhibition of total MEK and total Akt, while total ERK levels remained unchanged. Interestingly, signaling arrays also identified multiple other potential targets, as phosphorylated Akt, mTOR, and PTEN were suppressed by sorafenib. Conclusions: Our results demonstrate that sorafenib suppresses proliferation and invasion of DTs via inhibition of ERK signaling, with additional involvement of the mTOR signaling pathway. Sorafenib may be a potential therapeutic option in the treatment of desmoid tumors. Additional studies to examine the efficacy of combination therapy with sorafenib and a PI3K inhibitor are warranted. Citation Format: Laura M. Rosenberg, Monica M. Bertagnolli, Nancy L. Cho. Sorafenib suppresses desmoid tumor growth and invasion via inhibition of ERK signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3794. doi:10.1158/1538-7445.AM2014-3794