Abstract B115: Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes

Autor: Kevin Marks, Peili Zhang, Katya Marjon, Zenon D. Konteatis, Yesim Tuncay, Mark Fletcher, Marc L. Hyer, Everton Mandley, Jeremy Travins, Peter Kalev, Elia Aguado-Fraile
Rok vydání: 2019
Předmět:
Zdroj: Molecular Cancer Therapeutics. 18:B115-B115
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-19-b115
Popis: Methylthioadenosine phosphorylase (MTAP) is the enzyme in the methionine salvage pathway that metabolizes the byproduct of polyamine biosynthesis, 5′-methylthioadenosine (MTA). The MTAP gene is deleted in approximately 15% of all human cancers and results in accumulation of MTA that partially inhibits protein arginine methyl transferase 5 (PRMT5) function. Recent studies have demonstrated that loss of the MTAP gene sensitizes cancer cells to genetic depletion of PRMT5 and the upstream metabolic enzyme methionine adenosyltransferase 2 alpha (MAT2A). We have developed a first-in-class, highly potent, orally bioavailable MAT2A inhibitor, AG-270, which is currently under investigation in a phase 1 clinical trial (ClinicalTrials.gov NCT03435250). AG-270 selectively inhibits the growth of HCT116 MTAP-/- cells compared to HCT116 MTAP+/+ cells in vitro and in vivo. We utilized RNA sequencing and proteomic approaches to study the underlying mechanism of action for AG-270. The results of these analyses demonstrated that AG-270 treatment induces substantial splicing changes in an MTAP selective manner. The majority of these abnormal splicing events were detained introns, which included genes involved in cell cycle regulation and DNA damage response. Moreover, AG-270 treatment resulted in accumulation of DNA damage and increased mitotic defects in HCT116 MTAP-/- cells. Furthermore, we demonstrated substantially advantageous combination benefits between AG-270 and anti-mitotic taxanes in in vitro cell lines and in in vivo patient-derived xenograft models of non-small cell lung, pancreatic and esophageal cancers. These findings uncover relevant combination strategies targeting MTAP-deleted malignancies, and provide preclinical mechanistic proof-of-concept to explore such combinations in the clinical setting. Citation Format: Peter Kalev, Marc L Hyer, Mark Fletcher, Peili Zhang, Elia Aguado-Fraile, Everton Mandley, Yesim Tuncay, Zenon Konteatis, Jeremy Travins, Kevin M Marks, Katya Marjon. Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes [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 B115. doi:10.1158/1535-7163.TARG-19-B115
Databáze: OpenAIRE
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