RT Journal Article
SR Electronic
T1 AraC-FdUMP[10] Is a Next-Generation Fluoropyrimidine with Potent Antitumor Activity in PDAC and Synergy with <em>PARG</em> Inhibition
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP 565
OP 572
DO 10.1158/1541-7786.MCR-20-0985
VO 19
IS 4
A1 Haber, Alex O.
A1 Jain, Aditi
A1 Mani, Chinnadurai
A1 Nevler, Avinoam
A1 Agostini, Lebaron C.
A1 Golan, Talia
A1 Palle, Komaraiah
A1 Yeo, Charles J.
A1 Gmeiner, William H.
A1 Brody, Jonathan R.
YR 2021
UL http://mcr.aacrjournals.org/content/19/4/565.abstract
AB AraC-FdUMP[10] (CF10) is a second-generation polymeric fluoropyrimidine that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard-of-care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple cell lines including patient-derived lines) with IC50s in the nanomolar range and are nearly 1,000-fold more potent than 5-FU. The increased potency of CF10 relative to 5-FU correlated with enhanced TS inhibition and strong Top1 cleavage complex formation. Furthermore, CF10 displayed single-agent activity in PDAC murine xenografts without inducing weight loss. Through a focused drug synergy screen, we identified that combining CF10 with targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase, induces substantial DNA damage and apoptosis. This work moves CF10 closer to a clinical trial for the treatment of PDAC.Implications: CF10 is a promising polymeric fluoropyrimidine with dual mechanisms of action (i.e., TS and Top1 inhibition) for the treatment of PDAC and synergizes with targeting of DNA repair.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/4/565/F1.large.jpg.This article is featured in Highlights of This Issue, p. 541