Accession Number : AD1050872


Title :   Targeting BRCAness in Gastric Cancer


Descriptive Note : Technical Report,15 Sep 2016,14 Sep 2017


Corporate Author : Indiana University Indianapolis United States


Personal Author(s) : Collisson,Eric ; Quigley,David ; Wu,Wei ; Fong,Lawrence ; Ashworth,Alan ; OLeary,Patrick ; Woods,Jefferson ; Diolaiti,Morgan ; Yelena,Janjigian ; Tuvy,Yaelle ; Vakiani,Evsevia ; Korn,W M ; Mirzoeva,Olga


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1050872.pdf


Report Date : 01 Oct 2017


Pagination or Media Count : 19


Abstract : We performed the screen of gastric cancer cell lines for their sensitivity to small molecule inhibitors of PARP (rucaparib, talazoparib, olaparib, AZD2461) alone, or in combination with MEK inhibitors. We also generated a modified CRISPR system using dCas9-KRAB expressing variants of these cells, and validated them for CRISPRi screening. These reagents will next be used for a sensitization screen to PARPi, ATRi and MEKi treatment. In the drug response assays, cell lines differed dramatically in their sensitivity and resistance to these drugs. A subset of gastric cancer cells showed synergistic response to a combination of PARPi olaparib or talazoparib with MEK inhibitor GSK1120212 (trametinib), while the other cells were resistant to one or to both PARPi and MEKi. The predictive mechanism of cellular response is currently under study. We compared DNA damage signaling in gastric cancer cell lines. Pretreatment of cells with MEKiabolished activation of ATM and BRCA1 induced by either PARPi or the DNA-damaging agent Etoposide. Synergistic cell lines displayed downregulation of DNA damage-induced phospho-H2Ax and phospho-ATM when pretreated with MEKi. This effect was pronounced higher when the cells were pretreated with a combination of PARPi and MEKi.


Descriptors :   STOMACH , cancer , carcinoma , neoplasms , inhibitors , therapy , cell physiological processes , drug combinations , mutations , culture techniques , resistance (biology) , cell line , dna , repair , gene expression


Subject Categories : Medicine and Medical Research
      Pharmacology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE