Panobinostat (LBH589), a pan-DAC inhibitor, induces cell death in ER+ and HER2 amplified cell lines in vitro and is synergistic in vivo with trastuzumab

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 2_Supplement; p. 4047
• Main Authors: Finn, RS, Shao, W, Dering, J, Ginther, C, Kalous, O, Conklin, D, Cohen, DJ, Desai, A, Yai, Y, Atadja, P, Slamon, DJ
• Format: Journal Article
• Language: English
• Published: 15.01.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS-4047

Abstract Abstract #4047 Background: Histone modifications have been investigated as causing altered gene expression resulting in activation of oncogenic pathways. Panobinostat (LBH589) is a potent pan-deacetylase (DAC) inhibitor in clinical development. Given the potentially broad biological effects of this class of agent, we assessed the in vitro effects of panobinostat on a large panel of molecularly profiled human breast cancer cell lines to better define the differential effects of panobinostat across subtypes and to help guide clinical development. In addition, preclinical studies evaluated the effects of panobinostat and the HER2-targeted antibody, trastuzumab.
 Methods: 43 human cell lines representing known molecular subgroups of breast cancer, and 3 immortalized breast lines were treated in duplicate with panobinostat using two-fold dilutions over 12 concentrations. Dose response curves were generated using a cell count assay to calculate IC50 and LD50 of panobinostat. Data were analyzed against baseline gene expression data (Agilent microarray) to identify genes associated with sensitivity (S) and resistance (R) to panobinostat. 12 cell lines (6 S; 6 R) were then treated with clinically relevant concentrations of panobinostat; RNA was isolated after 48 hrs. Agilent expression profiles compared pre-and post-treatment cell lines to identify differentially expressed genes (DEGs) that change in S and R cell lines. In vivo, nude mice bearing HER2+ and pathway-dependent BT-474 xenografts were treated with panobinostat alone and in combination with trastuzumab. Tumor growth inhibition and delay were measured.
 Results: In vitro panobinostat has potent anti-proliferative effects across all breast cancer subtypes with most IC50 values <100nM. When analyzed by effects on cell death, luminal ER+ and HER2 amplified cell lines were more sensitive to lethality than non-luminal subtypes using a cut-off of LD50 50nM (Chi-square<0.05 for subtype). Of interest, the non-malignant, immortalized lines were very resistant (LD50 >1000nM), which suggests some differential activity in malignant cell lines versus those that are more “normal”. When gene expression profiles were analyzed pre-and post-treatment, a remarkable overlap was seen in number and specific genes changing after panobinostat exposure in both S and R lines. However, the degree of gene changes was greater in S lines than R lines. In vivo, panobinostat acted synergistically with trastuzumab to inhibit growth of the HER2 amplified breast cancer cell line, BT-474.
 Conclusion: These studies suggest that ER+ and HER2 amplified breast cancers may be more likely to respond to the pan-DAC inhibitor panobinostat. Profiling studies identified 218 DEGs that were significantly changed between S and R lines. These data support the ongoing development of panobinostat in breast cancer and provide rationale for patient selection. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4047.