Abstract A063: TAS1553, a novel class of RNR inhibitor, demonstrates synergistic antitumor efficacy in combination with nucleoside analogues

Abstract

Abstract Background: Ribonucleotide reductase (RNR) is an essential metabolic enzyme that catalyzes a rate-limiting step for de novo dNTP biosynthesis via converting ribonucleotides to deoxyribonucleotides. dNTPs are also supplied through nucleoside salvage pathway in which dNTP is synthesized from extracellular nucleoside. The salvage pathway is also utilized for conversion of several nucleoside analogues to their active metabolites. Given the previous report showing that the inhibition of de novo pathway activates salvage pathway at least in vitro, RNR is considered as a promising target for combination therapy with nucleoside analogues. However, in vivo efficacy of selective RNR inhibitor in combination with nucleoside analogues has not been clarified yet. Previously, we reported a novel class of RNR inhibitor TAS1553, which is a selective and orally available small molecule abrogating protein-protein interaction between RNR subunits. Here, we evaluated the synergistic activity of TAS1553 and several nucleoside analogues in vitro as well as in vivo studies. Material and methods: Antiproliferative activity was assessed by CellTiter-Glo® 2.0 assay. Intracellular and intratumoral ara-CTP amounts were measured by HPLC analysis. Antitumor efficacy was evaluated in athymic nude mice bearing MV-4-11 (human AML) and CFPAC-1 (human pancreatic cancer) cell line. Results: To examine whether TAS1553 plus nucleoside analogues combination shows synergistic efficacy, we evaluated antiproliferative activity of TAS1553 in combination with some nucleoside analogues (cytarabine, gemcitabine, decitabine, and 2F-ara-A) to calculate the combination index (CI). TAS1553 exhibited synergistic antiproliferative activity (CI < 1) against cancer cell lines in combination with all of the tested nucleoside analogues. Then, to analyze the mechanism underlying the synergistic effect, we asked whether treatment with TAS1553 augments the activity of salvage pathway by measuring ara-CTP, which is an active metabolite of cytarabine. The results showed that treatment with TAS1553 significantly increased ara-CTP accumulation in MV-4-11 cells implying that TAS1553 activates nucleoside salvage pathway by inhibiting de novo nucleotide synthesis. Importantly, when analyzing the timing of treatment for the combination, prior or simultaneous treatment with TAS1553 increased ara-CTP amount more than post treatment. Consistently with in vitro result, co-administration of TAS1553 and cytarabine caused significant increase of intratumoral ara-CTP compared with cytarabine administration in MV-4-11 mouse xenograft model. Following this result, the combination of TAS1553 (100 mg/kg/day, q.d.) and cytarabine (10 mg/kg/day, 5 consecutive days) showed superior antitumor efficacy to MV-4-11 tumor than each monotherapy while the combination did not cause intolerable body weight change. Furthermore, TAS1553 also demonstrated the striking anittumor efficacy in combination with gemcitabine (20 mg/kg/day, q.wk.) on CFPAC-1 mouse xenograft model. Conclusions: TAS1553, a novel class of RNR inhibitor, has synergistic antitumor efficacy in combination with nucleoside analogues. These combination therapy could be promising therapeutic options for cancer patients. Citation Format: Takuya Hoshino, Hiroyuki Ueno, Wakako Yano, Sayaka Tsukioka, Seiji Miyahara, Takamasa Suzuki, Kazutaka Miyadera, Teruhiro Utsugi, Takeshi Sagara. TAS1553, a novel class of RNR inhibitor, demonstrates synergistic antitumor efficacy in combination with nucleoside analogues [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A063. doi:10.1158/1535-7163.TARG-19-A063