CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

David Gallo, Jordan T. F. Young, Jimmy Fourtounis, Giovanni Martino, Alejandro Álvarez-Quilón, Cynthia Bernier, Nicole M. Duffy, Robert Papp, Anne Roulston, Rino Stocco, Janek Szychowski, Artur Veloso, Hunain Alam, Prasamit S. Baruah, Alexanne Bonneau Fortin, Julian Bowlan, Natasha Chaudhary, Jessica Desjardins, Evelyne Dietrich, Sara Fournier, Chloe Fugère-Desjardins, Theo Goullet de Rugy, Marie-Eve Leclaire, Bingcan Liu, Vivek Bhaskaran, Yael Mamane, Henrique Melo, Olivier Nicolas, Akul Singhania, Rachel K. Szilard, Ján Tkáč, Shou Yun Yin, Stephen J. Morris, Michael Zinda, C. Gary Marshall () and Daniel Durocher ()
Additional contact information
David Gallo: Mount Sinai Hospital
Jordan T. F. Young: Repare Therapeutics
Jimmy Fourtounis: Repare Therapeutics
Giovanni Martino: Repare Therapeutics
Alejandro Álvarez-Quilón: Mount Sinai Hospital
Cynthia Bernier: Repare Therapeutics
Nicole M. Duffy: Repare Therapeutics
Robert Papp: Repare Therapeutics
Anne Roulston: Repare Therapeutics
Rino Stocco: Repare Therapeutics
Janek Szychowski: Repare Therapeutics
Artur Veloso: Repare Therapeutics
Hunain Alam: Repare Therapeutics
Prasamit S. Baruah: Repare Therapeutics
Alexanne Bonneau Fortin: Repare Therapeutics
Julian Bowlan: Repare Therapeutics
Natasha Chaudhary: Mount Sinai Hospital
Jessica Desjardins: Repare Therapeutics
Evelyne Dietrich: Repare Therapeutics
Sara Fournier: Repare Therapeutics
Chloe Fugère-Desjardins: Repare Therapeutics
Theo Goullet de Rugy: Mount Sinai Hospital
Marie-Eve Leclaire: Repare Therapeutics
Bingcan Liu: Repare Therapeutics
Vivek Bhaskaran: Repare Therapeutics
Yael Mamane: Repare Therapeutics
Henrique Melo: Mount Sinai Hospital
Olivier Nicolas: Repare Therapeutics
Akul Singhania: Repare Therapeutics
Rachel K. Szilard: Mount Sinai Hospital
Ján Tkáč: Mount Sinai Hospital
Shou Yun Yin: Repare Therapeutics
Stephen J. Morris: Repare Therapeutics
Michael Zinda: Repare Therapeutics
C. Gary Marshall: Repare Therapeutics
Daniel Durocher: Mount Sinai Hospital

Nature, 2022, vol. 604, issue 7907, 749-756

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04638-9

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