Targeting resistance against the MDM2 inhibitor RG7388 in glioblastoma cells by the MEK inhibitor trametinib

• Verfasst von: Berberich, Anne [VerfasserIn]
• Verfasst von: Keßler, Tobias [VerfasserIn]
• Verfasst von: Pusch, Stefan [VerfasserIn]
• Verfasst von: Sahm, Felix [VerfasserIn]
• Verfasst von: Schmitt, Lara-Marie [VerfasserIn]
• Verfasst von: Fischer, Manuel [VerfasserIn]
• Verfasst von: Lemke, Dieter [VerfasserIn]
• Verfasst von: Breckwoldt, Michael O. [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Verfasst von: Bendszus, Martin [VerfasserIn]
• Verfasst von: Platten, Michael [VerfasserIn]
• Verfasst von: Wick, Wolfgang [VerfasserIn]
• Titel: Targeting resistance against the MDM2 inhibitor RG7388 in glioblastoma cells by the MEK inhibitor trametinib
• Verf.angabe: Anne Berberich, Tobias Kessler, Carina M. Thomé, Stefan Pusch, Thomas Hielscher, Felix Sahm, Iris Oezen, Lara-Marie Schmitt, Sara Ciprut, Nanina Hucke, Petra Ruebmann, Manuel Fischer, Dieter Lemke, Michael O. Breckwoldt, Andreas von Deimling, Martin Bendszus, Michael Platten, and Wolfgang Wick
• Jahr: 2019
• Jahr des Originals: 2018
• Umfang: 13 S.
• Fussnoten: Gesehen am 30.04.2019 ; Published online first October 1, 2018
• Titel Quelle: Enthalten in: Clinical cancer research
• Ort Quelle: Philadelphia, Pa. [u.a.] : AACR, 1995
• Jahr Quelle: 2019
• Band/Heft Quelle: 25(2019), 1, Seite 253-265
• ISSN Quelle: 1557-3265
• DOI: doi:10.1158/1078-0432.CCR-18-1580
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1663804796

Abstract

Purpose: Resistance is an obstacle of glioma therapy. Despite targeted interventions, tumors harbor primary resistance or become resistant over short course of treatment. This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma. - Experimental Design: Effects of RG7388 and radiotherapy were analyzed in p53 wild-type glioblastoma cell lines and glioma-initiating cells. RG7388 resistant cells were generated by increasing RG7388 doses over 3 months. Regulated pathways were investigated by microarray, qRT-PCR, and immunoblot analysis and specifically inhibited to evaluate rational salvage therapies at RG7388 resistance. Effects of RG7388 and trametinib treatment were challenged in an orthotopical mouse model with RG7388 resistant U87MG glioblastoma cells. - Results: MDM2 inhibition required functional p53 and showed synergistic activity with radiotherapy in first-line treatment. Long-term exposure to RG7388 induced resistance by activation of the extracellular signal-regulated kinases 1/2 (ERK1/2)–insulin growth factor binding protein 1 (IGFBP1) signaling cascade, which was specifically overcome by ERK1/2 pathway inhibition with trametinib and knockdown of IGFBP1. Combining trametinib with continued RG7388 treatment enhanced antitumor effects at RG7388 resistance in vitro and in vivo. - Conclusions: These data provide a rationale for combining RG7388 and radiotherapy as first-line therapy with a specific relevance for tumors insensitive to alkylating standard chemotherapy and for the addition of trametinib to continued RG7388 treatment as salvage therapy after acquired resistance against RG7388 for clinical practice.