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.
Competing Interest Statement
DD is a shareholder and advisor of Repare Therapeutics. DD also received research funding from Repare Therapeutics for this study. DG is funded by Repare Therapeutics. JTFY, JF, GM, CB, ND, RP, AR, RS, JS, AV, PB, ABF, JB, JD, ED, SF, TGR, MEL, BL, ON, AS, SYY, SJM, MZ and CGM are employees of Repare Therapeutics. HA and CFD were employees of Repare Therapeutics.
