Targeting erbB Pathways in Breast Cancer: Dual Kinase Inhibition for Brain Metastasis and Prevention of p185HER2/Neu Tumor Development

Peeyush N Goel,1,2,* Makoto Katsumata,3,* Wei Qian,4 Sunil Mathur,4 Mei Q Ji,1 Arabinda Samanta,1 Payal Grover,1 George Sgouros,5 Jenny C Chang,4 Mark I Greene1 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6082, USA; 2Children’s Hospital of Philadelphia, Philadelphia, PA, 19104-6082, USA; 3Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; 4Dr. Mary and Ron Neal Cancer Center, Houston Methodist Hospital, Houston, TX, USA; 5The Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA*These authors contributed equally to this workCorrespondence: Mark I Greene, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 252 John Morgan Building, 3620 hamilton Walk, Philadelphia, PA, 19104, USA, Tel +215-898-2847, Email [email protected]: Breast cancer predominantly affects women and poses challenges in the treatment of both local and advanced diseases. In a previous study, we reported the effectiveness of ER121, a structurally resolved small compound specifically designed to target human cancers expressing or overexpressing mutant EGFR and HER2.Purpose: The objective of this study is to assess the efficacy and toxicity of ER121 in metastatic and triple negative breast cancer (TNBC, HER2+) cells and tumor models. The Herceptin-resistant breast cancer cell line JIMT-1 was used in an in vivo tumor model, and MMTV-erbB2 (Fo5) transgenic mice models were used to evaluate the efficacy and safety of ER121 as neoadjuvant.Methods: ER121 treatment focusing on experimental brain metastasis in TNBC, HER2+ model, was quantified by total flux employing the In Vivo Imaging System (IVIS). We also compared the brain tissue from the treated and the controls groups. Additionally, ER121 was evaluated in JIMT-1, a Herceptin-resistant breast cancer cell line, both in vitro and in vivo tumor model. We also administered ER121 orally in neoadjuvant model with the MMTV-erbB2 (Fo5) transgenic mice, the survival rates were compared with the control group. Tumor-free survival of multiple treated groups were analyzed by Kaplan-Meier analysis employing the log-rank test with the Bonferroni correction using R Statistical Software.Results: In this study, we present findings indicating that ER121 treatment significantly attenuated breast tumor growth using a TNBC, HER2+ model, focusing on experimental brain metastasis, as quantified by total flux employing IVIS. These observations were further corroborated by analysis of brain tissue from the treatment group compared to controls. Data is presented as Mean ± S.D. statistical significance was calculated using Student t test (*p