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000181935 1001_ $$0P:(DE-He78)11a5984ad9d927df64e2bd688545375f$$aRösch, Lisa$$b0$$eFirst author$$udkfz
000181935 245__ $$aERBB and P-glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P-glycoprotein.
000181935 260__ $$aHoboken, NJ$$bJohn Wiley & Sons, Inc.$$c2023
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000181935 500__ $$a#EA:B310#LA:B310# / 2023 Jan;17(1):37-58
000181935 520__ $$aChemotherapy resistance is a persistent clinical problem in relapsed high-risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P-glycoprotein (P-gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, i.e., dephosphorylation of the downstream pathways upon afatinib treatment but direct off-target interference with P-gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P-gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P-gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.
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000181935 650_7 $$2Other$$aapoptotic cell death
000181935 650_7 $$2Other$$achemotherapy resistance
000181935 650_7 $$2Other$$aoff-target
000181935 650_7 $$2Other$$apediatric patient samples
000181935 650_7 $$2Other$$aprecision medicine
000181935 650_7 $$2Other$$azebrafish xenograft model
000181935 7001_ $$0P:(DE-He78)ea170691ed65b95f10820c4c61d6e2cd$$aHerter, Sonja$$b1$$udkfz
000181935 7001_ $$0P:(DE-He78)f08873535c440e3ce033c84d5786f70f$$aNajafi, Sara$$b2$$udkfz
000181935 7001_ $$0P:(DE-He78)53112ef656923758316e7079710bc988$$aRidinger, Johannes$$b3$$udkfz
000181935 7001_ $$0P:(DE-He78)2727b5cb63b52d0137d4f4e8f110ee7e$$aPeterziel, Heike$$b4$$udkfz
000181935 7001_ $$aCinatl, Jindrich$$b5
000181935 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b6$$udkfz
000181935 7001_ $$aMichaelis, Martin$$b7
000181935 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b8$$udkfz
000181935 7001_ $$0P:(DE-He78)908367a659dea9e28dac34592b3c46e5$$aOehme, Ina$$b9$$eLast author$$udkfz
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