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Cell Rep. 2019 Apr 9;27(2):631-647.e5. doi: 10.1016/j.celrep.2019.03.045.

High-Complexity shRNA Libraries and PI3 Kinase Inhibition in Cancer: High-Fidelity Synthetic Lethality Predictions.

Author information

1
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeroen.roose@ucsf.edu.

Abstract

Deregulated signal transduction is a cancer hallmark, and its complexity and interconnectivity imply that combination therapy should be considered, but large data volumes that cover the complexity are required in user-friendly ways. Here, we present a searchable database resource of synthetic lethality with a PI3 kinase signal transduction inhibitor by performing a saturation screen with an ultra-complex shRNA library containing 30 independent shRNAs per gene target. We focus on Ras-PI3 kinase signaling with T cell leukemia as a screening platform for multiple clinical and experimental reasons. Our resource predicts multiple combination-based therapies with high fidelity, ten of which we confirmed with small molecule inhibitors. Included are biochemical assays, as well as the IPI145 (duvelisib) inhibitor. We uncover the mechanism of synergy between the PI3 kinase inhibitor GDC0941 (pictilisib) and the tubulin inhibitor vincristine and demonstrate broad synergy in 28 cell lines of 5 cancer types and efficacy in preclinical leukemia mouse trials.

KEYWORDS:

GDC0941; PI3 kinase; cancer; inhibitors; leukemia; preclinical mouse trials; screen; shRNA; signaling pathways; synthetic lethality; vincristine

PMID:
30970263
DOI:
10.1016/j.celrep.2019.03.045
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