Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR

Haineng Xu; Erin George; David Gallo; Sergey Medvedev; Xiaolei Wang; Rosie Kryczka; Marc L Hyer; Jimmy Fourtounis; Rino Stocco; Elia Aguado-Fraile; Adam Petrone; Shou Yun Yin; Ariya Shiwram; Matthew Anderson; Hyoung Kim; Fang Liu; C Gary Marshall; Fiona Simpkins

doi:10.21203/rs.3.rs-3854682/v1

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR

Res Sq [Preprint]. 2024 Feb 16:rs.3.rs-3854682. doi: 10.21203/rs.3.rs-3854682/v1.

Authors

Haineng Xu^{1

2}, Erin George^{1

2}, David Gallo³, Sergey Medvedev^{1

2}, Xiaolei Wang^{1

2}, Rosie Kryczka³, Marc L Hyer⁴, Jimmy Fourtounis³, Rino Stocco³, Elia Aguado-Fraile⁴, Adam Petrone⁴, Shou Yun Yin³, Ariya Shiwram³, Matthew Anderson^{1

2}, Hyoung Kim^{1

2}, Fang Liu^{1

2}, C Gary Marshall⁴, Fiona Simpkins^{1

2}

Affiliations

¹ Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
² Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA.
³ Repare Therapeutics, Inc., 7171 Frederick-Banting, Ville St-Laurent, QC, Canada.
⁴ Repare Therapeutics, Cambridge, MA, USA.

Abstract

Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with CCNE1-amplification are often resistant to standard of care treatment and represent an unmet clinical need. Previously, synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with CCNE1-amplification. We hypothesized that CCNE1-amplification associated replication stress will be more effectively targeted by combining the PKMYT1 inhibitor, lunresertib (RP-6306), with the ATR inhibitor, camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increased cytotoxicity more in CCNE1 amplified compared to non-amplified cells. Combination treatment produced durable antitumor activity and increased survival in CCNE1 amplified patient-derived and cell line-derived xenografts. Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is a novel therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

Keywords: ATR; CCNE1 amplification; PKMYT1.

Publication types

Preprint

Abstract

Publication types

Grants and funding