CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition.

Autor: Gallo D; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Young JTF; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fourtounis J; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Martino G; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Álvarez-Quilón A; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Bernier C; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Duffy NM; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Papp R; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Roulston A; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Stocco R; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Szychowski J; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Veloso A; Repare Therapeutics, Cambridge, MA, USA., Alam H; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Baruah PS; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fortin AB; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Bowlan J; Repare Therapeutics, Cambridge, MA, USA., Chaudhary N; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Desjardins J; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Dietrich E; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fournier S; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fugère-Desjardins C; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Goullet de Rugy T; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Leclaire ME; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Liu B; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Bhaskaran V; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Mamane Y; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Melo H; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Nicolas O; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Singhania A; Repare Therapeutics, Cambridge, MA, USA., Szilard RK; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Tkáč J; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Yin SY; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Morris SJ; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Zinda M; Repare Therapeutics, Cambridge, MA, USA., Marshall CG; Repare Therapeutics, Cambridge, MA, USA. gmarshall@reparerx.com., Durocher D; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. durocher@lunenfeld.ca.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. durocher@lunenfeld.ca.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Apr; Vol. 604 (7907), pp. 749-756. Date of Electronic Publication: 2022 Apr 20.
DOI: 10.1038/s41586-022-04638-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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