Hsieh Antony, Pitarresi Jason R, Lerner Jonathan, Donahue Greg, Hsiehchen David, Rustgi Anil K, Zaret Kenneth
Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104-5157, USA.
Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104-5157, USA.
Sci Adv. 2020 Dec 4;6(49). doi: 10.1126/sciadv.abc4517. Print 2020 Dec.
Here, we selectively target pancreatic ductal adenocarcinoma (PDAC) cells harboring a hemizygous gene essential for cell growth. (), encoding a chromatin-bound protein, is hemizygous in most of the PDAC due to a chromosome 17p deletion that also spans We find that hemizygous loss in isogenic PDAC cells promotes tumorigenesis but, paradoxically, homozygous loss is associated with impaired cell growth and decreased tumorigenesis. Poly-adenosine 5'-diphosphate-ribose polymerase 1 (PARP1) interacts with MYBBP1A and displaces it from chromatin. Small molecules, such as olaparib, that trap PARP1 to chromatin are able to evict the minimal pool of chromatin-bound MYBBP1A protein in hemizygous cells and impair cell growth, greater than its impact on wild-type cells. Our findings reveal how a cell essential gene with one allele lost in cancer cells can be preferentially susceptible to a specific molecular therapy, when compared to wild-type cells.
在此，我们选择性地靶向携带对细胞生长至关重要的半合子基因的胰腺导管腺癌（PDAC）细胞。（）编码一种与染色质结合的蛋白质，由于17号染色体p缺失（该缺失也跨越……），在大多数PDAC中为半合子状态。我们发现，在同基因PDAC细胞中半合子缺失促进肿瘤发生，但矛盾的是，纯合子缺失与细胞生长受损和肿瘤发生减少有关。聚腺苷酸5'-二磷酸-核糖聚合酶1（PARP1）与MYBBP1A相互作用并将其从染色质上置换下来。诸如奥拉帕尼之类的小分子，可将PARP1捕获到染色质上，能够清除半合子细胞中与染色质结合的MYBBP1A蛋白质的最小池，并损害细胞生长，其对细胞生长的影响大于对野生型细胞的影响。我们的研究结果揭示了与野生型细胞相比，癌细胞中一个等位基因缺失的细胞必需基因如何能优先对特定分子疗法敏感。
