2. Academic Validation
  3. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

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

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. gmarshall@reparerx.com.
  • 5 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. durocher@lunenfeld.ca.
  • 6 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. durocher@lunenfeld.ca.
  • # Contributed equally.
PMID: 35444283 DOI: 10.1038/s41586-022-04638-9
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145817A
    99.90%, PKMYT1抑制剂
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