Elimusertib (BAY1895344), a novel ATR inhibitor, demonstrates in vivo activity in ATRX mutated models of uterine leiomyosarcoma

Justin Harold, Stefania Bellone, Diego D. Manavella, Levent Mutlu, Blair McNamara, Tobias Max Philipp Hartwich, Margherita Zipponi, Yang Yang-Hartwich, Cem Demirkiran, Miguel Skyler Verzosa, Jungmin Choi, Weilai Dong, Natalia Buza, Pei Hui, Gary Altwerger, Gloria S. Huang, Vaagn Andikyan, Mitchell Clark, Elena Ratner, Masoud AzodiPeter E. Schwartz, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy. Recent data suggest 50% of uLMS may harbor alterations in the ATRX gene and such mutations may confer sensitivity to ataxia-telangiectasia-and-Rad3-related (ATR) kinase inhibitors. We sought to investigate the in vivo activity of Elimusertib (BAY1895344), a novel ATR-inhibitor, against ATRX-mutated uLMS patient-derived xenografts (PDXs). Methods: Two fully characterized uLMS (i.e., LEY-11 and LEY-16) were grafted into female CB-17/SCID mice. Treatments with control vehicle or BAY1895344 (20 mg/kg dosed twice daily 3 days on 4 days off) were given via oral gavage and tumor measurements as well as weights obtained twice weekly. Tumor volume differences were calculated with a two-way ANOVA. Mechanistic studies were performed ex vivo using BAY1895344 treated uLMS tumor samples by western blot analysis. Results: Both PDX LEY-11 and PDX LEY-16 harboring ATRX gene mutations demonstrated an aggressive behavior in vivo (i.e., control mice were euthanized on average at day 12.5 for PDX LEY-11 and at day 33 for PDX LEY-16). In both tumor models BAY1895344 20 mg/kg dosed with an intermittent oral schedule was able to induce significant growth inhibition compared to vehicle control treatment (p < 0.001 for both LEY-11 and LEY-16) and prolong median overall survival [PDX LEY-11 (12.5 vs. 42 days, p < 0.001) and PDX LEY-16 (33 vs. 60 days, p < 0.001)]. There were not significant changes in weight between treatment and controls. By western blot assays BAY1895344 exposure decreased phosphorylated-ATR and increased expression of apoptotic molecules in LMS PDXs. Conclusions: BAY1895344 demonstrates promising in vivo activity against biologically aggressive PDX models of uLMS harboring ATRX mutations, with no significant toxicity. Clinical trials of BAY1895344 in uLMS patients are warranted.

Original languageEnglish
Pages (from-to)157-165
Number of pages9
JournalGynecologic Oncology
Volume168
DOIs
Publication statusPublished - 2023 Jan

Keywords

  • ATR inhibitors
  • ATRX
  • BAY1895344
  • DAXX
  • Uterine leiomyosarcoma

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

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