title: Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM.
abstract: Several small molecules that inhibit the PI3 kinase (PI3K)-Akt signaling pathway are in clinical development. Although many of these molecules have been effective in preclinical models, it remains unclear whether this strategy alone will be sufficient to interrupt the molecular events initiated and maintained by signaling along the pathways because of the activation of other pathways that compensate for the inhibition of the targeted kinase. In this study, we performed a synthetic lethality screen to identify genes or pathways whose inactivation, in combination with the PI3K inhibitors PX-866 and NVPBEZ-235, might result in a lethal phenotype in glioblastoma multiforme (GBM) cells. We screened GBM cells (U87, U251, and T98G) with a large-scale, short hairpin RNA library (GeneNet), which contains 43 800 small interfering RNA sequences targeting 8500 well-characterized human genes. To decrease off-target effects, we selected overlapping genes among the 3 cell lines that synergized with PX-866 to induce cell death. To facilitate the identification of potential targets, we used a GSE4290 dataset and The Cancer Genome Atlas GBM dataset, identifying 15 target genes overexpressed in GBM tissues. We further analyzed the selected genes using Ingenuity Pathway Analysis software and showed that the 15 genes were closely related to cancer-promoting pathways, and a highly interconnected network of aberrations along the MYC, P38MAPK, and ERK signaling pathways were identified. Our findings suggest that inhibition of these pathways might increase tumor sensitivity to PX-866 and therefore represent a potential clinical therapeutic strategy.
authors.affiliation: Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yong-Wan
authors.initials: YW
authors.lastname: Kim
authors.forename: Ta Jen
authors.initials: TJ
authors.lastname: Liu
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: Ningyi
authors.initials: N
authors.lastname: Tiao
authors.forename: Abdullah H
authors.initials: AH
authors.lastname: Feroze
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004338:Drug Combinations; D015195:Drug Design; D004357:Drug Synergism; D005804:Genes, Lethal; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics*; D006067:Gonanes / Q000494:pharmacology*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D004338:Drug Combinations; D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering