CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

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 MMB-FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

编码细胞周期蛋白E（cyclin E，CCNE1）的基因扩增是多种恶性肿瘤的致癌驱动事件，并与化疗耐药及不良预后密切相关。为挖掘CCNE1扩增型肿瘤的潜在治疗靶点，我们在CCNE1扩增的细胞模型中开展了全基因组CRISPR/Cas9介导的合成致死筛选。本研究发现，CCNE1表达水平升高会赋予细胞对PKMYT1激酶（CDK1的负调控因子）抑制作用的易感特性。为靶向抑制PKMYT1，我们开发了RP-6306——一种具备口服生物利用度的选择性抑制剂，其在CCNE1扩增模型中可展现单药抗肿瘤活性，且与吉西他滨联合使用时可实现持久的肿瘤消退。RP-6306处理可在CCNE1过表达细胞中选择性诱导CDK1异常激活，促使正在进行DNA复制的细胞提前进入有丝分裂。CCNE1过表达至少部分通过提前激活MMB-FOXM1有丝分裂转录程序，破坏CDK1的稳态平衡。综上，PKMYT1抑制是CCNE1扩增型癌症极具前景的治疗策略。