Abstract 585: PTEN is a critical determinant in sensitizing cells to γ-secretase inhibitors

Abstract

Abstract Phase I studies of gamma secretase inhibitors (GSIs) that block Notch signaling have indicated clinical activity, especially in patients with sarcomas and melanoma. None of these patients had activating mutations, yet they showed intrinsic sensitivity to the drug. Therefore, an understanding of the mechanisms for de novo sensitivity and resistance to this class of drugs would be critical for drug development. Towards this end, we treated a panel of human melanoma and sarcoma cells lines with JC-34, a potent inhibitor of gamma secretase. Even though all the cell lines showed inhibition of cleaved Notch 1 and suppression of Hes1 luciferase, only some of the cell lines showed inhibition of growth or induction of apoptosis. The sensitive cell lines also underwent G1 cell cycle arrest. In addition, all the sensitive cell lines were characterized by induction of PTEN and suppression of p-AKT (473) after the administration of JC-34. Melanoma cell lines with wild type PTEN were sensitive (SKMEL 32 and SKMEL 267) while PTEN mutant/ null cells were insensitive (SKMEL 39 and 133). In order to further assess the impact of PTEN status upon drug susceptibility, we compared the impact of JC-34 upon isogenic breast cancer cell lines that differ only in PTEN status. In the breast cancer cell line MDAMB468, proliferation inhibition was approximately 50% in the presence of PTEN expression compared to 10% in MDAB468 cells without PTEN expression. In this system, induction of apoptosis was a significant contributor to inhibition of proliferation. Taken together, these data suggest that the status of PTEN before and/or after drug treatment may play a critical role in determining tumor susceptibility to Notch pathway inhibition. As PTEN is negatively regulated by Notch, modulation of PTEN status by GSIs may provide a rationale means to explain sensitivity of this class of drugs to particular subsets of tumor. This hypothesis will be validated in planned clinical trials with GSIs in patients with these diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2011-585