小柯机器人

加拿大西奈山医院Daniel Durocher等合作发现，CCNE1扩增是PKMYT1激酶抑制的合成致死性扩增。2022年4月20日出版的《自然》杂志发表了这一成果。

为了研究CCNE1扩增肿瘤的治疗靶点，他们在CCNE1扩增的细胞模型中进行了基于基因组规模CRISPR–Cas9的合成致死性筛选。他们报告，增加CCNE1剂量会导致PKMYT1激酶的抑制，PKMYT1激酶是CDK1的负调节因子。为了抑制PKMYT1，他们开发了RP-6306，这是一种选择性抑制剂，在CCNE1扩增模型中与吉西他滨联合使用时，显示出单药活性和持久的肿瘤消退。RP-6306处理导致CCNE1过度表达细胞中CDK1选择性非计划激活，促进DNA合成细胞的早期有丝分裂。CCNE1过表达至少部分通过MMB–FOXM1有丝分裂转录程序的早期激活破坏CDK1稳态。他们得出结论，PKMYT1抑制是治疗CCNE1扩增癌的一种有前途的策略。

据介绍，染色体19q12上CCNE1基因座的扩增在多种肿瘤类型中普遍存在，尤其是在高级别浆液性卵巢癌、子宫肿瘤和胃食管癌中，其中高细胞周期蛋白E水平与基因组不稳定性、全基因组加倍以及对细胞毒性和靶向治疗的耐药性有关。

附：英文原文

Title: CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

Author: Gallo, David, Young, Jordan T. F., Fourtounis, Jimmy, Martino, Giovanni, lvarez-Quiln, Alejandro, Bernier, Cynthia, Duffy, Nicole M., Papp, Robert, Roulston, Anne, Stocco, Rino, Szychowski, Janek, Veloso, Artur, Alam, Hunain, Baruah, Prasamit S., Fortin, Alexanne Bonneau, Bowlan, Julian, Chaudhary, Natasha, Desjardins, Jessica, Dietrich, Evelyne, Fournier, Sara, Fugre-Desjardins, Chloe, Goullet de Rugy, Theo, Leclaire, Marie-Eve, Liu, Bingcan, Bhaskaran, Vivek, Mamane, Yael, Melo, Henrique, Nicolas, Olivier, Singhania, Akul, Szilard, Rachel K., Tk, Jn, Yin, Shou Yun, Morris, Stephen J., Zinda, Michael, Marshall, C. Gary, Durocher, Daniel

Issue&Volume: 2022-04-20

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 therapies1,2,3,4. 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.

DOI: 10.1038/s41586-022-04638-9

Source: https://www.nature.com/articles/s41586-022-04638-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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