Abstract 459: Targeting MUC1 mediated nucleotide metabolism sensitizes pancreatic tumors to radiation therapy

Abstract

Abstract Pancreatic cancer has the lowest survival rate of six perecent among all the cancers in the US and is projected to be the second leading cause of cancer related deaths in a decade. Radiation therapy provides only marginal increases in the survival rate in pancreatic cancer, due to poor responsiveness of pancreatic tumors. Clinical trials indicate a significant response to radiation only in twenty percent of primary pancreatic tumors. While multiple factors cause resistance to radiation therapy, the biological mechanisms mediating such innate resistance are currently being explored. Overexpression of MUC1 facilitates chemo and radiation resistance in pancreatic cancer. MUC1 overepxression also promotes pancreatic tumor growth through metabolic upregulation. We investigated the in vivo role of MUC1 mediated metabolic alterations in radiation response of pancreatic tumors. Our findings indicate that MUC1 expressing pancreatic tumors survive better upon radiation treatment. Metabolomic analysis through liquid chromatography coupled tandem mass spectrometry approach revealed that MUC1 expressing pancreatic tumors exhibit higher glycolytic and nucleotide metabolites upon irradiation. MUC1 expressing tumors also possess relatively higher PPP and nucleotide metabolites. Glycolytic inhibition using bromopyruvate revealed that MUC1 induced radiation resistance could be abrogated through inhibition of glucose carbon flux into nucleotide metabolism by BrPA. Treatment with BrPA effectively reduced glycolysis, pentose phosphate pathway and nucleotide levels in irradiated MUC1 expressing cells. Furthermore, a combination of BrPA and radiation reduced tumor growth in MUC1 expressing tumors. Metabolomic analysis showed a decrease in the glycolysis, PPP and nucleotide metabolites in MUC1 expressing tumors upon combination treatment with radiation and BrPA. Hence, our findings demonstrate that glycolytic inhibition could be used to effectively target MUC1 mediated radiation-resistance in pancreatic tumors. Citation Format: VENUGOPAL GUNDA, Joshua Souchek, Jaime Abrego, Gennifer Goode, Enza Vernucci, Surendra K. Shukla, Aneesha DasGupta, Nina V. Chaika, Ryan King, Fang Yu, Tadayoshi Bessho, Chi Lin, Wang Shou, Li Sicong, Pankaj K. Singh. Targeting MUC1 mediated nucleotide metabolism sensitizes pancreatic tumors to radiation therapy [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 459. doi:10.1158/1538-7445.AM2017-459