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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