5-Flurouracil (5-FU) is a mainstay of colorectal cancer therapy. Even though much is known about the 5-FU mechanism of action, very little is known about the genetic determinants which provide sensitivity and resistance to 5-FU. Here we provide first insights into p53, a major predictor of 5-FU response, modulating nucleotide catabolism specifically through the control of the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD). Colorectal cancer cells expressing mtp53 specifically show higher expression of DPYD as compared to the wildtype p53 (wtp53) carrying cells. Higher expression of DPYD in mtp53 cells specifically provides increased resistance to 5-FU as indicated by cellular proliferation and long term clonogenic assays. Furthermore, knockdown of DPYD in mtp53 cells preferentially resensitizes them to 5-FU as opposed to cells expressing Wtp53 by decreasing the viability and increasing apoptosis observed in these cells. Pharmacological inhibition of DPYD with gimeracil, clinical inhibitor of 5-FU phenocopies the effects seen by siRNA/shRNA mediated knockdown of DPYD. Finally, invivo studies with tumor xenograft from mtp53 carrying cells shown increase resistance to 5-FU therapy which is abrogated by stable knockdown of DPYD expression or in combination gimeracil. Preliminary analysis of TCGA patients treated with 5-FU indicate differential expression of DPYD based on specific Tp53 mutation status. Taken together our study provides first insights into crosstalk between nucleotide catabolism and mtp53 under conditions of DNA damage and metabolic stress having major implications on the therapeutic response to 5-FU the in the clinic.

Citation Format: Prashanth Ravishankar Gokare, Niklas Finnberg, David Dicker, Maureen Murphy. Didhydropyrimdine dehydrogenase (DPYD) provides resistance to 5-flurouracil in mutant p53 (mtp53) expressing colorectal cancer cells [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 96. doi:10.1158/1538-7445.AM2017-96