Abstract 4407: Inhibition of STAT3 in primary trastuzumab-resistant HER2-positive cells leads to decrease cell viability

Abstract

Abstract Breast Cancer is the second leading cause of cancer related death in women. Approximately, 20%-30% of breast cancer patients overexpress Human Epidermal Growth Factor Receptor 2 (HER2). HER2 Is a Tyrosine Kinase receptor involved in proliferation and survival and its overexpression makes it a good target for patients with HER2 positive breast cancer. Trastuzumab (TRA) is a recombinant monoclonal antibody that binds HER2 receptor and inhibits its signaling. Unfortunately, clinical studies have demonstrated that 30% of patients that overexpress HER2 do not respond to Trastuzumab treatment. Therefore, understanding the molecular mechanisms underlying Trastuzumab resistance is essential to develop new therapies to treat these breast cancer patients. Previous studies in our lab demonstrated that a decrease in cell growth of HER2 overexpressing cells occurred when IGF2 and HER2 were inhibited. Nevertheless, these cells overcame the growth inhibition and the resulting proliferative growth coincided with an increase in STAT3 activation. STAT3 is a transcription factor that promotes cell proliferation and can regulate apoptosis in cancer cells. These findings lead us to hypothesize that blocking STAT3 together with IGF2 and HER2 will inhibit proliferation and cell viability of Trastuzumab resistant breast cancer cells. We treated Trastuzumab-resistant HER2 positive JIMT1 cells with HER2, IGF2, and/or STAT3 inhibitors. After 24 hours of treatment, there was a marked difference in cell morphology observed between the treatment groups. Cell viability was measured using WST-1, a reagent that measures mitochondrial activity. A significant decrease in cell viability was observed when cells were treated for 24 hours with a commercially available STAT3 inhibitor (Sttatic). There was no difference between the treatment groups when STAT3 was inhibited by Stattic or when STAT3 was inhibited in combination with IGF2 and/or HER2 inhibitors. These findings suggest that in Trastuzumab-resistant HER2 positive JIMT1 cells, STAT3 activation overcomes the inhibition of the HER2 and IGF2 proliferation pathways resulting in cell death prevention. Our study demonstrate that Trastuzumab-resistant HER2 positive JIMT1 cells can activate STAT3 as an alternative pathway to evade apoptosis and promote chemoresistance. Our data also illustrate the challenge of treating cancer based on single therapies since tumors have many alternative pathways to promote growth. Citation Format: Xousaen M. Helu, Alfida Fernandez, Daisy D. De Leon. Inhibition of STAT3 in primary trastuzumab-resistant HER2-positive cells leads to decrease cell viability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4407.