Dataset Information

Activation of STAT3 through SRC and EGFR Drives Resistance to a Mitotic Kinesin Inhibitor in Glioblastoma

ABSTRACT: The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.The outcome for patients afflicted with glioblastoma (GBM), the most common and malignant of primary brain tumors in adults, has changed little despite decades of clinical, translational, and basic research. Any effective, systemically administered GBM therapy needs to target cellular components that are indispensable for the malignant phenotype with drugs that cross the blood brain barrier (BBB) and have manageable toxicities. However, while a number of signaling pathways have been shown to drive the malignant phenotype in GBM, and while relatively non-toxic, CNS permeant inhibitors of several of these have been identified, their efficacy in GBM has been disappointing. In this study, we examine the mechanism of resistance to the Kif11 inhibitor ispinesib in murine and human GBM. We find that development of resistance in these tumors occurs by a mechanism not previously described for Kif11 inhibitors, is associated with broad scale transcriptomic and phenotypic changes, and can be reversed with drugs that are FDA approved or in clinical investigation. Our findings also point to ways of enhancing the efficacy of Kif11 inhibitors that are directly translatable into a clinical setting.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Glioblastoma

SUBMITTER: Lauren Stopfer

LAB HEAD: Forest White

PROVIDER: PXD030715 | Pride | 2023-05-10

REPOSITORIES: Pride

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			Action	DRS
	20171105_pTyrAnalysis.mzML	Mzml
	20171105_pTyrAnalysis.mzid.gz	Mzid
	20171105_pTyrAnalysis.raw	Raw
	20171107_Supernatant_Normalization.mzML	Mzml
	20171107_Supernatant_Normalization.mzid.gz	Mzid

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Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma.

Kenchappa Rajappa S RS Dovas Athanassios A Argenziano Michael G MG Meyer Christian T CT Stopfer Lauren E LE Banu Matei A MA Pereira Brianna B Griffith Jessica J Mohammad Afroz A Talele Surabhi S Haddock Ashley A Zarco Natanael N Elmquist William W White Forest F Quaranta Vito V Sims Peter P Canoll Peter P Rosenfeld Steven S SS

Cell reports 20220601 12

Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of ...[more]

PMID: 35732128

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Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term âtumor initiating cellsâ (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models. Gamma-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. In this study we employed two of such inhibitors, namely the z-Leu-leu-Nle-CHO (LLNle) and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to verify whether they were effective in vitro in the killing of human GBM tumor initiating cells (TICs). We first established that of the two drugs only LLNle reduces the viability of GBM TICs obtained from three different patients in the low micromolar range. Cells were treated with 7.5 Î¼M LLNle or DAPT or vehicle alone (DMSO 0.1%) and kept in a humidified 5% CO2 atmosphere at 37Â°C for the indicated time period (24 or 48 hours). To establish which cellular processes are activated in GBM TICs by LLNle we generated and analyzed the gene expression profile after treatment with this compound and with DAPT and DMSO (vehicle). Our data show that LLNle induces upregulation of genes coding for proteasome subunits and subsequently mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activation of genes acting as mitotic inhibitors. Our data are consistent with proteasome inhibition by LLNle, subsequent upregulation of proteasome activity and subsequent unleash of the apoptotic process in GBM TICs.