Inhibition Of Her2 And Igf2 In Trastuzumab-Resistant Her2 Positive Jimt1 Cells Decreases Cell Growth And Reduces Activation Of Mapk And Akt

Breast cancer is the second leading cause of death in women. Overexpression of human epidermal growth factor receptor 2 (HER2) is detected in 20-30% of breast cancers. Increased levels of HER2 are linked to poor prognosis, more aggressive phenotype, and resistance to chemotherapy and hormonal treatment. HER2 is part of a four-member family of cell surface receptors that are implicated in transmission of signals controlling cell growth and differentiation. HER2 has an intracellular domain with tyrosine kinase catalytic activity. Dimerization of HER2 activates the MAPK and AKT pathways. The HER2 receptor also hetero-dimerizes with the IGF1 receptor (IGF1R) in trastuzumab-resistant cells. The insulin-like growth factor 2 (IGF2) has an important role in fetal and cancer development signaling through the IGF1R, insulin receptor (InsR), and a cross-talk with the estrogen receptors alpha and beta (ERα, ERs). Trastuzumab resistance occurs in 70% of patients with HER2 positive breast cancer. Therefore it is important to understand the mechanism of resistance so we can develop new therapies to help patients with trastuzumab-resistant rumors. Previous findings in our lab demonstrate an increased expression of IGF2 in the trastuzumab-resistant cell line JIMT1 when compared to trastuzumab-sensitive cell lines BT474, SKBR3, and ZR75-30. We hypothesize that to overcome trastuzumab-resistance in JIMT1 cells, dual inhibition of the HER2 and IGF2 is necessary to induce cell death. When JIMT1 cells were treated with trastuzumab and an IGF2 blocking antibody (IBA) a decrease in cell viability was observed, but changes in PARP cleavage were not present. We also analyzed the protein and phosphorylation levels of HER2, IGF1R, MAPK, and AKT. Our studies suggest that blocking both HER2 and IGF2 decreases cell viability and reduces phosphorylation of MAPK and AKT. Citation Format: Xousaen M. Helu, Daisy DeLeon. Inhibition of HER2 and IGF2 in trastuzumab-resistant HER2 positive JIMT1 cells decreases cell growth and reduces activation of MAPK and AKT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3919. doi:10.1158/1538-7445.AM2015-3919