Functional Genomic Analysis of CDK4 and CDK6 Gene Dependency across Human Cancer Cell Lines.
Functional Genomic Analysis of CDK4 and CDK6 Gene Dependency across Human Cancer Cell Lines.
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人类癌细胞系中CDK4和CDK6基因依赖性的功能基因组分析
DOI：
10.1158/0008-5472.can-21-2428
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发表时间：
2022-06-06
期刊：
影响因子：
11.2
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中科院分区：
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细胞周期蛋白依赖蛋白4(CDK4)和细胞周期蛋白依赖性蛋白6(CDK6)是细胞周期的关键调节因子，在人类恶性肿瘤中经常发生异常调节。CDK4/6抑制剂已被临床批准用于激素受体阳性、HER2阴性(HR+/HER2−)乳腺癌的治疗，但特异性的提高和毒性的降低可能会扩大它们的用途到其他适应症。通过对可公开获得的全基因组功能丧失数据的分析，结合单靶向和双靶向CRISPR分析，我们发现细胞系对CDK4单独缺失、CDK6单独缺失、CDK4/CDK6联合缺失或两者都不缺失的细胞增殖易感性不同。CDK6表达是CDK4(负相关)和CDK6(正相关)依赖关系的最佳单项预测因子，腺癌细胞对CDK4缺失更敏感，血液和鳞癌细胞对CDK6缺失更敏感。Rb-E2F信号通路在这些实验中被证实是CDK4/6的主要下游节点，从RB1缺失的存活效应可以看出这一点。最后，我们在一个不依赖CDK4/6的癌细胞亚群中表明，CDK2-CCNE1是细胞增殖的一个重要的替代依赖。总之，我们的全面数据探索和功能实验描绘了泛癌CDK4/6基因依赖的图景，并确定了可能对CDK4或CDK6选择性抑制剂敏感的独特癌细胞群体。
Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key cell cycle regulators that are frequently dysregulated in human malignancies. CDK4/6 inhibitors are clinically approved for the treatment of hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer, but improved specificity and reduced toxicity might expand their use to other indications. Through analysis of publicly available genome-wide loss-of-function data combined with single and dual-targeting CRISPR assays, we found differential cell proliferation vulnerability of cell lines to either CDK4 deletion alone, CDK6 deletion alone, combined CDK4/CDK6 deletion, or neither. CDK6 expression was the best single predictor of CDK4 (negatively correlated) and CDK6 (positively correlated) dependencies in the cancer cell lines, with adenocarcinoma cell lines being more sensitive to CDK4 deletion and hematologic and squamous cancer cell lines being more sensitive to CDK6 deletion. RB-E2F signaling was confirmed as a main downstream node of CDK4/6 in these experiments as shown by the survival effects of RB1 deletion. Finally, we show in a subset of cancer cell lines not dependent on CDK4/6 that CDK2-CCNE1 is an important alternative dependency for cell proliferation. Together, our comprehensive data exploration and functional experiments delineate the landscape of pan-cancer CDK4/6 gene dependencies and define unique cancer cell populations that might be sensitive to CDK4-selective or CDK6-selective inhibitors.