Abstract A242: A novel AKT inhibitor, PH427, prevents UVB-induced signaling in human squamous skin carcinomas.

Abstract

Abstract Non-melanoma skin cancers (NMSC) are a significant and increasing health problem in the United States that occur primarily on sun-exposed areas of the body and are strongly associated with chronic sun exposure. Recent advances in our understanding of the molecular basis of carcinogenesis have lead to the identification of potential molecular targets that might be used to prevent the progression of early skin cancer. AKT (protein kinase B), a pleckstrin homology (PH) lipid binding domain and a serine/threonine kinase containing protein is a key component of the phophatidylinositol-3-kinase (PtdIns3-K) cell survival signaling pathway which is activated in skin cancers. In this study, we describe the effects of a novel inhibitor of AKT (PH427) that binds to the PH domain of AKT thus preventing its binding to PtIns-(3,4,5)P3 at the plasma membrane and subsequent activation. PH427 inhibits AKT activity at low micromolar concentrations in HaCat human keratinocytes and HaCat-II,4, a ras transformed human keratinocyte cell line. We demonstrate that PH427 is able to prevent UVB-induced AKT activation and expression in both cell lines. PH427 also induced apoptosis in both HaCat and HaCat II,4 keratinocytes. Moreover, the compound is lipophilic and penetrates the skin in SKH-1 mice when applied topically. Short term in vitro studies showed that PH427 prevents UVB-induced AKT activation and UVB-induced signaling, as measured by p70S6 Kinase and p-GSK3-activation. Long-term in vivo studies utilizing SKH-1 mice have also shown significant reduction of UVB-induced skin tumors when PH427 is topically applied when compared to acetone-only control or PH427 alone. Additionally, drug treated mice exhibit reduced levels of phospho-Ser473AKT in the epidermal layers. We conclude that the topical application of PH427 may be beneficial for preventing NMSC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A242.