Abstract
Simple SummaryGlioblastoma (GBM) remains a particularly challenging cancer, with an aggressive phenotype and few promising treatment options. Future therapy will rely heavily on diagnosing and targeting aggressive GBM cellular phenotypes, both before and after drug treatment, as part of personalized therapy programs. Here, we use a genome-wide drug-induced gene expression (DIGEX) approach to define the cellular drug response phenotypes associated with two clinical drug candidates, the phosphodiesterase 10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib. We identify genes encoding specific drug targets, some of which we validate as effective antiproliferative agents and combination therapies in human GBM cell models, including HMGCoA reductase (HMGCR), salt-inducible kinase 1 (SIK1), bradykinin receptor subtype B2 (BDKRB2), and Janus kinase isoform 2 (JAK2). Individual, personalized treatments will be essential if we are to address and overcome the pharmacological plasticity that GBM exhibits, and DIGEX will play a central role in validating future drugs, diagnostics, and possibly vaccine candidates for this challenging cancer.We have used three established human glioblastoma (GBM) cell lines—U87MG, A172, and T98G—as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come.
Highlights
Glioblastoma (GBM) is characterized by pronounced cellular heterogeneity, with different glioblastoma cell lineages presumed to emanate from glioma stem cells (GSCs) within the same patient tumor [1]
We extend these detailed observations to a suite of three well-characterized GBM cell lines—U87MG, A172, and T98G—and two further growth inhibitory drugs in the clinic, the phosphodiesterase 10A (PDE10A) inhibitor Mardepodect (PF-02545920) and the multi-protein kinase inhibitor Regorafenib (Stivarga, BAY 73-4506)
Established cell lines, while possessing lengthy passage histories, provide well characterized, robust and relatively reproducible systems in which to compare drug responses, and studies with them have provided the bulk of the information we have on drug response in GBM
Summary
Glioblastoma (GBM) is characterized by pronounced cellular heterogeneity, with different glioblastoma cell lineages presumed to emanate from glioma stem cells (GSCs) within the same patient tumor [1]. Using singlecell RNA sequencing, individual tumor cells can be positioned within a spectrum spanning proneural to mesenchymal cell types, with the mesenchymal phenotype correlating with significantly poorer patient survival [4]. Tumor-initiation studies with cell surface marker-enriched GBM populations, xenografted into immunodeficient mouse models, show that these cells retain their capability to re-form the full spectrum of proneural to mesenchymal phenotypes observed in the original patient tumors [5], emphasizing the phenotypic plasticity and stem-like characteristics of GBM tumor cells. Despite an increasing understanding of the molecular evolution of such tumors, and the development of powerful new approaches such as immunotherapy to target them, GBM clinical outcomes remain poor [7]. New drug and vaccine targets which translate into effective therapies are urgently required
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