TY  - JOUR
AU  - Krausert, Sonja
AU  - Brabetz, Sebastian
AU  - Mack, Norman L
AU  - Schmitt-Hoffner, Felix
AU  - Schwalm, Benjamin
AU  - Peterziel, Heike
AU  - Mangang, Aileen
AU  - Holland-Letz, Tim
AU  - Sieber, Laura
AU  - Korshunov, Andrey
AU  - Oehme, Ina
AU  - Jäger, Natalie
AU  - Witt, Olaf
AU  - Pfister, Stefan M
AU  - Kool, Marcel
TI  - Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma.
JO  - Neuro-oncology advances
VL  - 4
IS  - 1
SN  - 2632-2498
CY  - Oxford
PB  - Oxford University Press
M1  - DKFZ-2022-01000
SP  - vdac026
PY  - 2022
N1  - #EA:B062#LA:B062# / 2022 Mar 13;4(1):vdac026
AB  - Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlying resistance mechanisms and to find ways to overcome the resistance, preclinical models that became resistant to SMO inhibition are needed.To induce SMO inhibitor resistant tumors, we have treated a patient-derived xenograft (PDX) model of SHH medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg Sonidegib using an intermitted treatment schedule. Vehicle-treated and resistant models were subjected to whole-genome and RNA sequencing for molecular characterization and target engagement. In vitro drug screens (76 drugs) were performed using Sonidegib-sensitive and -resistant lines to find other drugs to target the resistant lines. One of the top hits was then validated in vivo.Nine independent Sonidegib-resistant PDX lines were generated. Molecular characterization of the resistant models showed that eight models developed missense mutations in SMO and one gained an inactivating point mutation in MEGF8, which acts downstream of SMO as a repressor in the SHH pathway. The in vitro drug screen with Sonidegib-sensitive and -resistant lines identified good efficacy for Selinexor in the resistant line. Indeed, in vivo treatment with Selinexor revealed that it is more effective in resistant than in sensitive models.We report the first human SMO inhibitor resistant medulloblastoma PDX models, which can be used for further preclinical experiments to develop the best strategies to overcome the resistance to SMO inhibitors in patients.
KW  - SHH Medulloblastoma (Other)
KW  - SMO inhibitor (Other)
KW  - Selinexor (Other)
KW  - Sonidegib (Other)
KW  - resistance (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35475274
C2  - pmc:PMC9034118
DO  - DOI:10.1093/noajnl/vdac026
UR  - https://inrepo02.dkfz.de/record/179951
ER  -