Abstract
Abstract Paclitaxel is a first line treatment option for patients with metastatic breast cancer. However, inherited or acquired resistance is a limiting factor for therapy with paclitaxel. The mechanism of paclitaxel resistance remains obscured and hinders the development of therapeutic strategies. HER2 is an oncogene overexpressed in about 30% of breast cancer patients and plays role in drug resistance leading to poor prognosis. To identify more clinically relevant mechanism of paclitaxel resistance, we developed resistance to paclitaxel in MCF-7 and 4T1 breast cancer cell lines. The continuous exposure to paclitaxel for several months resulted in >1000 fold resistance in MCF-7 cells and >100 fold resistance in 4T1 cells. Western blot analysis showed enhanced expression of HER2, β-catenin and downstream molecules such as TCF/LEF, c-Myc, Cyclin D in these resistant cells. We have recently demonstrated that penfluridol, an anti-psychotic drug, suppresses the growth of triple negative metastatic breast cancer cells (Ranjan and Srivastava, Cancer Res 2016; 76(4): 877-890), giving us the rationale to evaluate whether penfluridol inhibits HER2 and β-catenin signaling. Our current results showed that penfluridol treatment not only suppressed HER2 but also inhibited β-catenin expression. We also observed down regulation of LEF-1/TCF, Cyclin D1 and c-Myc expression with penfluridol treatment in paclitaxel sensitive as well as resistant cells resulting in reduced survival of cells. Our results further showed that penfluridol treatment synergistically enhanced the growth suppressive effects of paclitaxel in MCF-7 and 4T1 paclitaxel resistant cells. Treatment of paclitaxel resistant 4T1 cells with 1.5μM of penfluridol in combination with 50nM of paclitaxel resulted in 65% of cell growth suppression whereas either treatment alone was not cytotoxic at all. We also observed an enhanced down regulation of proteins involved in paclitaxel resistance such as HER2, β-catenin, c-Myc and Cyclin D1 as well as increase in apoptotic markers such as Cl-PARP and Cl-Caspase3 when paclitaxel treatment was combined with penfluridol in resistant cells. Taken together, our results provided a novel insight into the mechanism of resistance to paclitaxel and also opened new avenues for application of penfluridol in cancer therapeutics. Further detailed mechanistic and in vivo studies are in progress. (Supported in part by RO1 grant CA129038, awarded by National Cancer Institute, NIH). Citation Format: Nehal Gupta, Parul Gupta, Sanjay Srivastava. Inhibition of HER2/β-catenin signaling by penfluridol overcomes resistance to paclitaxel in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3176. doi:10.1158/1538-7445.AM2017-3176
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