Effective Targeting of Triple Negative Breast Cancer Cells by PF-4942847, a Novel Oral Inhibitor of Heat Shock Protein 90
Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'efficacité d'un inhibiteur de la protéine de choc thermique 90 sur des cellules de cancer du sein triple négatif
Purpose: Triple negative breast cancer (TNBC) patients have poor prognoses and survival outcomes such that the development of new targeted therapies is in strong demand. Mechanisms associated with high proliferation and aggressive tumor progression, such as PI3K/PTEN aberration, EGFR overexpression, and cell cycle up-regulation, play important roles in TNBC. The molecular chaperone heat shock protein 90 kDa (Hsp90) is required for the conformational maturation and stability of a variety of proteins in multiple pathways, such as EGFR, AKT, Raf, cdk4, etc. Therefore, an Hsp90 inhibitor may demonstrate therapeutic benefit in TNBC by targeting multiple pathways. Experimental Design: The novel oral Hsp90 inhibitor PF-4942847 was characterized in multiple in vitro and in vivo assays to determine its antitumor activity in TNBC cell lines. In addition, the correlation of AKT degradation and Hsp70 induction in host peripheral blood lymphocytes (PBLs) and xenograft tumors was determined. Results: PF-4942847 induces degradation of multiple client proteins, cell cycle block, apoptosis, and inhibits cell proliferation in TNBC lines, subsequently leading to tumor growth inhibition in mouse xenograft models. The correlation of AKT degradation and Hsp70 induction between PBLs and xenograft tumors reveals a differential modulation of Hsp90 activity between host and tumor tissues, and suggests that AKT degradation in PBLs may serve as a pharmacodynamic biomarker in future clinical development. Conclusions: The novel oral Hsp90 inhibitor, PF-4942847, is a candidate for clinical development in TNBC by collaboratively targeting multiple signaling pathways. Additionally, AKT degradation in PBLs may serve as a biomarker in clinical development.