Presentation Abstract

Abstract Number: 2820
Presentation Title: Vorinostat abrogates ridaforolimus-induced activation of Akt in synovial sarcoma cells: A possible rationale for their synergism
Presentation Time: Monday, Apr 02, 2012, 1:00 PM - 5:00 PM
Location: McCormick Place West (Hall F), Poster Section 31
Poster Section: 31
Poster Board Number: 25
Author Block: Sherif S. Morgan, Lee D. Cranmer. University of Arizona, Tucson, AZ
Abstract Body: Background: Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist and such patients have a poor prognosis. Previously, we demonstrated that the combination of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat exhibited synergism in a variety of cell lines. Here, we explore whether the Akt pathway is potentially involved in mediating the synergistic effects of ridaforolimus and vorinostat.
Methods: Two SS cell lines (HS-SY-II and SYO-I) were treated with the single agents or with combinations of ridaforolimus and vorinostat. After 72 hours, cell viability was measured using the cell proliferation assay (MTS). Combination Indices (CI) were calculated to determine whether each combination was synergistic, additive, or antagonistic. Western Blot analysis assessed alterations in total and phospho-Akt protein levels in response to drug treatment.
Results: Ridaforolimus IC50 was 10.9nM in HS-SY-II and 23.1nM in SYO-I; vorinostat IC50 was 440nM in HS-SY-II and 561nM in SYO-I. CI were 0.28 and 0.63 in HS-SY-II and SYO-I, respectively, indicating synergism between the two agents. The ridaforolimus/vorinostat combination was assessed in other tumor types, including osteosarcoma (U2OS), metastatic melanoma (Stew1 and Stew2), pancreatic cancer (Panc1 and BxPC3), and lung cancer (A549). The combination was synergistic in all cell lines: CI ranged from 0.37 to 0.77, except in Panc1, where it was additive (CI=0.92). As previously observed with other mTOR inhibitors, ridaforolimus alone increased pAkt-ser473 levels in SS cell lines; this effect was abrogated by the addition of vorinostat.
Conclusions: The combination of ridaforolimus and vorinostat demonstrates in vitro synergism in SS as well as in a variety of other tumor types. The addition of vorinostat prevented ridaforolimus-induced Akt activation, a possible mechanism of resistance to mTOR inhibition. Adding HDAC inhibition to mTOR inhibitors may be a route to circumvent Akt-mediated resistance to mTOR inhibitors. Our results also indicate that this combination may demonstrate broad anti-neoplastic activity.