CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

Nature. 2022 Apr;604(7907):749-756. doi: 10.1038/s41586-022-04638-9. Epub 2022 Apr 20.


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.

MeSH terms

  • CDC2 Protein Kinase
  • Cyclin E* / genetics
  • Female
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Proteins* / genetics
  • Neoplasms / genetics
  • Ovarian Neoplasms* / pathology
  • Protein Serine-Threonine Kinases* / genetics
  • Protein-Tyrosine Kinases* / genetics
  • Synthetic Lethal Mutations


  • CCNE1 protein, human
  • Cyclin E
  • Membrane Proteins
  • Protein-Tyrosine Kinases
  • PKMYT1 protein, human
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human