CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

Gallo, D.; Young, J. T. F.; Fourtounis, J.; Martino, G.; Alvarez-Quilon, A.; Bernier, C.; Duffy, N. M.; Papp, R.; Roulston, A.; Stocco, R.; Szychowski, J.; Veloso, A.; Alam, H.; Baruah, P. S.; Bonneau Fortin, A.; Bowlan, J.; Chaudhary, N.; Desjardins, J.; Dietrich, E.; Fournier, S.; Fugere-Desjardins, C.; Goullet de Rugy, T.; Leclaire, M.-E.; Liu, B.; Melo, H.; Nicolas, O.; Singhania, A.; Szilard, R. K.; Tkac, J.; Yin, S. Y.; Morris, S. J.; Zinda, M.; Marshall, C. G.; Durocher, D.

doi:10.1101/2021.04.08.438361

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bioRxiv · 10.1101/2021.04.08.438361

CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

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Abstract

Amplification of the gene encoding cyclin E (CCNE1) is an oncogenic driver in several malignancies and is associated with chemoresistance and poor prognosis. To uncover therapeutic targets for CCNE1-amplified tumors, 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 tumor 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 FOXM1/MYBL2/MuvB-dependent mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

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Gallo, D., Young, J. T. F., Fourtounis, J., Martino, G., Alvarez-Quilon, A., Bernier, C., Duffy, N. M., Papp, R., Roulston, A., Stocco, R., Szychowski, J., Veloso, A., Alam, H., Baruah, P. S., Bonneau Fortin, A., Bowlan, J., Chaudhary, N., Desjardins, J., Dietrich, E., Fournier, S., Fugere-Desjardins, C., Goullet de Rugy, T., Leclaire, M.-E., Liu, B., Melo, H., Nicolas, O., Singhania, A., Szilard, R. K., Tkac, J., Yin, S. Y., Morris, S. J., Zinda, M., Marshall, C. G., Durocher, D.. 2021-04-08. CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition. https://doi.org/10.1101/2021.04.08.438361

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