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. 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 therapies^1-4. 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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-145817A

lunresertib

99.90%, PKMYT1 Inhibitor

Wee1

Cancer

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