Abstract 2612: Effective targeting triple negative breast cancer cells by a novel oral heat shock protein 90 inhibitor PF-4942847

Abstract

Abstract Triple negative breast cancer (TNBC) patients have poor prognosis and survival that the development of new targeted therapies for TNBC is strongly demanded. Genes associated with high proliferation and aggressive tumor progression, such as PI3K/PTEN aberration, EGFR overexpression, and cell cycle upregulation, play important roles in triple negative breast cancer. The molecular chaperone heat shock protein 90 (Hsp90) is required for the conformational maturation and stability of a variety of key signaling proteins, such as EGFR, AKT, Raf, p53, and cdk4, in addition to many others. Therefore, an Hsp90 inhibitor may present therapeutic benefits on TNBC via the inhibition of EGFR, AKT/PI3K pathway, and cell cycle progression. In this study, we describe a novel oral Hsp90 inhibitor, PF-4942847, which induces apoptosis and cell cycle block, as well as inhibits cell proliferation in TNBC cells through protein degradation in EGFR, cMet, AKT, and pERK. PF-4942847 exhibits excellent oral bioavailability in mice and effectively induces Hsp90 client protein degradation in MDA-MB-231 xenograft tumors, and subsequently abolishes the in vivo tumor growth of MDA-MB-231 in the xenograft model. Moreover, correlation of AKT degradation and Hsp70 induction in host peripheral blood lymphocytes (PBLs) and xenograft tumors was determined and reveals a differential target modulation dynamic between Hsp90 client proteins in different tissue compartments. These data implicate AKT degradation in PBLs as a possible biomarker of tumor progression for future clinical development. In summary, our results demonstrate PF-4942847 is a potent oral Hsp90 inhibitor and is a candidate for clinical development in triple negative breast cancer by collaboratively targeting multiple signaling pathways. 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 2612. doi:10.1158/1538-7445.AM2011-2612