Combination drug screen targeting glioblastoma core vulnerabilities reveals pharmacological synergisms

Abstract

Synergistic drug combinations are an attractive anticancer strategy but prove challenging to identify. Here we present a stepwise approach consisting in revealing core cancer vulnerabilities and exploiting them through drug combination screen to uncover synergistic treatments for glioblastoma patients. Methods: We established an innovative method, based on high-throughput screening, target deconvolution and functional genomics, to reveal core vulnerabilities in glioblastoma. Combination drug screen targeting these vulnerabilities was then designed to unveil synergistic associations. The therapeutic potential of the top drug combination was validated in two different clinically-relevant models: an organotypic ex vivo model and a syngeneic orthotopic mouse model of glioblastoma. Results: Large-scale monotherapy drug screening identified 83 potent anti-glioblastoma compounds. Target deconvolution using public chemoinformatic databases uncovered 1,100 targets and interactors of the hit compounds. Screening of a focused siRNA library targeting the top 292 drug interactors revealed 22 targetable vulnerabilities, 9 of which were confirmed as core glioblastoma vulnerabilities by mining the CRISPR screen cohort data from the online Cancer Dependency Map portal. Six selective inhibitors of the core vulnerabilities were then screened in combination with a custom-made library of 88 compounds and synergies amongst the 528 tested pairwise combinations were predicted. The combinations of CHK1 / MEK and AURKA / BET inhibitors were highlighted and validated in 3D tumor spheroids. Using an organotypic ex vivo model and a syngeneic orthotopic mouse model, we definitively ascertained the efficacy of dual AURKA / BET inhibition in glioblastoma. Conclusions: Collectively, we uncovered that dual inhibition of BET proteins and aurora kinase A is highly synergistic against GBM. Moreover, our study indicates that our approach to exploit drug poly-pharmacology for the rational design of drug combination screens represent a valuable strategy to discover synergistic treatments against refractory cancers.

Aurora Kinase A Inhibition plus Tumor Treating Fields Suppress Glioma Cell Proliferation in a Cilium-Independent Manner

“…Further, while Alisertib has been shown by multiple groups to reach the brain and slow brain tumor growth in vivo as described above, a recent study examining Alisertib penetrance into CNS suggests its distribution and concentrations are limited (39). Supporting this observation, Alisertib treatment alone did not slow intracranial tumor growth of transplanted GL261glioma cells, but did synergize with co-treatment of Birabresib (a BET bromodomain inhibitor) to significantly extend survival(40). Thus it is feasible that low doses of Alisertib in the brain could combine or potentiate other drug or brain targeted therapies such as TTFields.…”

PARP inhibition enhances exemestane efficacy in triple-negative breast cancer

“…An alternative method to identify drug combinations is unbiased (or hypothesis-free) screening [17]. By utilizing chemical libraries alongside the drug of interest, this has the advantage of allowing for serendipitous discoveries and can facilitate greater understanding of the polypharmacology of drugs, where subsequent target deconvolution studies of a newly identified combination can reveal novel, sometimes unexpected, mechanisms of action [18]. Moreover, when an FDA-approved library is employed, clinical translation may be accelerated.…”