Activation of the mammalian target of rapamycin signaling pathway in hepatocellular carcinoma

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Activation of the Mammalian Target of Rapamycin Signaling Pathway in Hepatocellular Carcinoma

To the Editor:

We have read with great interest the article entitled “Sirolimus-Based Immunosuppression Is Associated with Increased Survival After Liver Transplantation for Hepatocellular Carcinoma” by Toso et al.1 The prospect of a dual role for inhibitors of mammalian target of rapamycin (mTOR), the so-called rapalogs, in both immunosuppression and chemotherapy will shape future therapy for hepatocellular carcinoma (HCC). We are writing now to draw attention to our institutional data reported by Li et al.,2 who evaluated mTOR expression in patients with HCC versus its expression in the cirrhotic liver and in normal liver tissue. These data show significantly elevated expression of p-mTOR in the sinusoidal endothelial cells of HCC tissue samples in comparison with non-HCC tissue (i.e., hepatic adenoma, cirrhotic nodules, and normal liver tissue), suggesting that this pathway plays a plausible role in HCC progression.

With several mTOR inhibitors in the clinic [sirolimus (rapamycin), everolimus (RAD001), and temsirolimus (CCI-779)], this immunohistological confirmation of elevated mTOR expression in HCC forms the rational foundation for signaling cascade activation–based targeted therapy with mTOR inhibitors. Moreover, a feedback loop pathway stemming from the use of mTOR, which leads to activation of the mitogen-activated protein kinase pathway, can be targeted by sorafenib3 (which is already in use and remains the only novel targeted drug demonstrating a survival benefit for patients with HCC). mTOR inhibitors have also shown promise in combination with other agents such as transarterial chemoembolization, adriamycin, and bevacizumab (Avastin)4, 5 in experimental preclinical models of HCC. We hope that novel “omics-based” techniques will unravel the mysteries of all the cell signaling pathways of each HCC with respect to the targeted therapy. We await with anticipation the outcomes of several ongoing phase 1 trials combining the next generation of mTOR, multikinase, and angiogenesis inhibitors (both small molecules and antibodies) for patients with HCC.

Ishwaria M. Mohan M.D., M.S.* †, Robert E. Brown M.D.‡, Michael B. Fallon M.D.†, * Divisions of Internal Medicine, University of Texas at Houston, Houston, TX, † Divisions of Pathology, University of Texas at Houston, Houston, TX, ‡ Divisions of Gastroenterology, Hepatology, and Nutrition, University of Texas at Houston, Houston, TX.

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