Survival of pancreatic cancer cells lacking KRAS function.,Nature Communications

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Survival of pancreatic cancer cells lacking KRAS function.
Nature Communications ( IF 14.7 ) Pub Date : 2017-10-23 , DOI: 10.1038/s41467-017-00942-5
Mandar Deepak Muzumdar _{1,

2,

3} , Pan-Yu Chen _{1,

4} , Kimberly Judith Dorans ₁ , Katherine Minjee Chung ₁ , Arjun Bhutkar ₁ , Erin Hong ₁ , Elisa M Noll _{5,

6} , Martin R Sprick _{5,

6} , Andreas Trumpp _{5,

6} , Tyler Jacks _{1,

4,

7}

Affiliation

Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.

中文翻译：

缺乏KRAS功能的胰腺癌细胞的存活。

原癌基因KRAS中的激活突变是胰腺导管腺癌（PDAC）的标志，它是一种侵袭性恶性肿瘤，几乎没有有效的治疗选择。尽管已努力开发针对KRAS的药物，但对PDAC细胞对KRAS的绝对依赖性仍未完全了解。在这里，我们使用CRISPR / Cas介导的基因组编辑对KRAS抑制进行建模，并证明KRAS在人和小鼠PDAC细胞的子集中是可有可无的。值得注意的是，几乎所有KRAS缺陷细胞均表现出磷酸肌醇3激酶（PI3K）依赖性的丝裂原活化蛋白激酶（MAPK）信号传导，并诱导了对PI3K抑制剂的敏感性。此外，比较保留或缺乏KRAS的PDAC细胞的基因表达谱，揭示了KRAS在抑制转移相关基因中的作用。总的来说，

更新日期：2017-10-23

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