Article

Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM

Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Neuro-Oncology (Impact Factor: 5.56). 04/2011; 13(4):367-75. DOI: 10.1093/neuonc/nor012
Source: PubMed

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.

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    • "Together, a number of recent studies have provided the molecular basis for the observation that small-molecule inhibitors of PI3K/Akt/mTOR signaling represent a potent strategy to enhance the sensitivity of cancer cells toward cell death induction via the mitochondrial pathway of apoptosis. Accordingly, smallmolecule inhibitors of PI3K/mTOR were shown to chemosensitize various cancers to a large variety of anticancer drugs, e.g., topoisomerase-1 or -2 inhibitors, platinum compounds, or microtubule interfering agents (Wallin et al., 2010; Bender et al., 2011; Kim et al., 2011; Mueller et al., 2012). This PI3K/mTOR-mediated chemosensitization may involve a shifted ratio between pro-and antiapoptotic Bcl-2 proteins, thereby engaging mitochondrial outer membrane permeabilization and the mitochondrial pathway of apoptosis. "
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    Preview · Article · Oct 2012 · Frontiers in Oncology
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    • "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. Attempts have recently been made 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 cells [48]. The identified shRNA22, when expressed in CSCs from glioblastoma patients, inhibits cell proliferation and self-renewal, induces apoptosis and significantly reduces their tumorigenic potential when xenotransplanted into the brains of nude rats. "
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