Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR.
Fiona SimpkinsHaineng XuErin GerogeDavid GalloSergey MedvedevXiaolei WangRosie KryczkaMarc HyerJimmy FourtounisRino StoccoElia Aguado-FraileAdam PetroneShou Yun YinAriya ShiwramMatthew AndersonHyoung KimFang LiuGary MarshallPublished in: Research square (2024)
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.
Keyphrases
- low dose
- dna damage
- cell cycle arrest
- cell cycle
- oxidative stress
- healthcare
- cancer therapy
- nucleic acid
- cell death
- randomized controlled trial
- clinical trial
- palliative care
- drug delivery
- high dose
- endometrial cancer
- cell proliferation
- health insurance
- pain management
- open label
- label free
- smoking cessation
- affordable care act