Abstract B55: mTOR signaling is critical to the development and expansion of preneoplastic foci in a rodent model of progenitor-marker positive hepatocellular carcinoma

Hepatocellular carcinoma is a heterogeneous disease with distinct tumor sub-types based on expression of markers for hepatocytes and adult liver progenitor cells, also known as oval cells. HCCs expressing progenitor cell markers have a poor prognosis. Relatively little is known about the signaling pathways underlying the molecular pathogenesis of these tumors. We have previously identified the mTOR pathway as playing a critical role in the proliferation of oval cells in rodents. In this study, we investigated the temporal activation of mTOR in a rodent animal model of progenitor marker-positive HCC. Rats were placed on the Solt-Farber protocol to induce hepatic carcinogenesis and mTOR activity assessed in preneoplastic and persistent focal lesions. Robust mTORC1 activity was found in early preneoplastic focal lesions with persistent focal lesions displaying minimal mTOR activity. Continuous administration of rapamycin resulted in a significant decrease in focal lesion burden, but led to an increase in PI3K signaling. Administration of rapamycin during the window of maximal mTOR activation significantly reduced focal lesion burden that was indistinguishable from that seen with continuous rapamycin administration. However, unlike continuous administration, short-term rapamycin administration did not result in compensatory activation of either PI3K or Erk1/2 signaling. We have also characterized the effect of short-term mTOR inhibition on the gene expression signature of the persistent preneoplastic foci. We conclude that mTOR activation is critical to the expansion and promotion of preneoplastic focal lesions in a rodent model of progenitor marker-positive HCC. These results raise the possibility that inhibition of mTOR early in the process of progenitor-derived hepatic carcinogenesis might serve as an effective preventative strategy for HCC. Citation Format: Heather Francois-Vaughan, Kate Brilliant, Adeola O. Adebayo, Nicola M.A. Parry, Philip A. Gruppuso, Jennifer A. Sanders. mTOR signaling is critical to the development and expansion of preneoplastic foci in a rodent model of progenitor-marker positive hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B55.