CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

  • Nature. 2022 Apr;604(7907):749-756. doi: 10.1038/s41586-022-04638-9.
David Gallo  #  1 Jordan T F Young  #  2 Jimmy Fourtounis  #  2 Giovanni Martino  2 Alejandro Álvarez-Quilón  1  2 Cynthia Bernier  2 Nicole M Duffy  2 Robert Papp  2 Anne Roulston  2 Rino Stocco  2 Janek Szychowski  2 Artur Veloso  3 Hunain Alam  2 Prasamit S Baruah  2 Alexanne Bonneau Fortin  2 Julian Bowlan  3 Natasha Chaudhary  1 Jessica Desjardins  2 Evelyne Dietrich  2 Sara Fournier  2 Chloe Fugère-Desjardins  2 Theo Goullet de Rugy  1  2 Marie-Eve Leclaire  2 Bingcan Liu  2 Vivek Bhaskaran  2 Yael Mamane  2 Henrique Melo  1 Olivier Nicolas  2 Akul Singhania  3 Rachel K Szilard  1 Ján Tkáč  1 Shou Yun Yin  2 Stephen J Morris  2 Michael Zinda  3 C Gary Marshall  4 Daniel Durocher  5  6
Affiliations
  • 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.
Abstract

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.

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