CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition
- Nature. 2022 Apr;604(7907):749-756. doi: 10.1038/s41586-022-04638-9.
- 1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
- 2. Repare Therapeutics, Saint-Laurent, Quebec, Canada.
- 3. Repare Therapeutics, Cambridge, MA, USA.
- 4. Repare Therapeutics, Cambridge, MA, USA. [email protected].
- 5. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. [email protected].
- 6. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [email protected].
- # Contributed equally.
Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian Cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies1-4. To uncover therapeutic targets for tumours with CCNE1 amplification, we undertook genome-scale CRISPR-Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here we report that increasing CCNE1 dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1 amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1-overexpressing cells, promoting early Mitosis in cells undergoing DNA synthesis. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB-FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.
-
Cat. No.Product NameDescriptionTargetResearch Area
-