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Sorafenib Suppresses Translation in Desmoid Tumors via Inhibition of mTOR Signaling.
Laura M. Rosenberg, MD1; Charles H. Yoon, MD, PhD2; Monica M. Bertagnolli, MD2; Nancy L. Cho, MD2
1Massachusetts General Hospital, Boston, MA; 2Brigham and Women's Hospital, Boston, MA

Background: Desmoid tumors (DTs) are mesenchymal tumors that occur sporadically or in association with familial adenomatous polyposis (FAP). Medical options are limited for recurrent or unresectable disease. Sorafenib is a multikinase inhibitor with known antitumor activity in various cancers. The PI3K-Akt-mTOR pathway is known to be a key regulator of translation involved in carcinogenesis. We have previously shown that sorafenib suppresses cell proliferation and invasion in desmoid-derived cells. Here, we examined the effects of sorafenib on DT cell lines, with the aim of better characterizing the mechanism of action of sorafenib in DTs.

Methods: DT-derived cells were cultured from patient tumor specimens, resulting in 15 distinct cell lines, from both sporadic and FAP patients. Cells were treated with sorafenib, and lysates were collected at intervals from 15 minutes to 3 days. Lysates were used for phosphoprotein signaling arrays and immunoblot analysis.

Results: Signaling arrays identified multiple potential targets of sorafenib in the PI3K-Akt-mTOR signaling cascade, with phosphorylated Akt and mTOR suppressed by sorafenib. Immunoblot analysis revealed that sorafenib inhibited p70S6K phosphorylation, and this effect correlated with inhibition of p-4E-BP1, p-eIF4E, and total eIF4E. Sorafenib also suppressed p-GSK-3-beta, active beta-catenin, and cyclinD1.

Conclusion: Our

Results: demonstrate that sorafenib suppresses the mTOR signaling cascade in desmoid-derived cells, suggesting that sorafenib may have antitumor activity in DTs due to inhibition of translation. Sorafenib also demonstrated inhibition of downstream targets of Wnt signaling, such as cyclinD1. Additional studies to examine the efficacy of combination therapy with sorafenib and an mTOR inhibitor are warranted.

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