Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma.
BMS754807
NRAS mutation
drug resistance
orthotopic sarcoma xenograft
pazopanib
synovial sarcoma
trametinib
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
22 Mar 2019
22 Mar 2019
Historique:
received:
05
02
2019
revised:
08
03
2019
accepted:
18
03
2019
entrez:
27
3
2019
pubmed:
27
3
2019
medline:
27
3
2019
Statut:
epublish
Résumé
Pazopanib is approved for treatment of advanced soft tissue sarcomas, but primary and secondary drug resistance limits its clinical utility. We investigated the molecular mechanisms mediating pazopanib resistance in human synovial sarcoma (SS) models. We found reduced cell sensitivity to pazopanib associated with inefficient inhibition of the two critical signaling nodes, AKT and ERKs, despite strong inhibition of the main drug target, PDGFRα. In the CME-1 cell line, overactivation of IGF1 and Insulin receptors (IGF1R/InsR) sustained AKT activation and pazopanib resistance, which was overcome by a combination treatment with the double IGF1R/InsR inhibitor BMS754807. In the highly pazopanib resistant MoJo cell line, NRASQ61R mutation sustained constitutive ERK activation. Transfection of the NRAS mutant in the pazopanib sensitive SYO-1 cell line increased the drug IC
Identifiants
pubmed: 30909453
pii: cancers11030408
doi: 10.3390/cancers11030408
pmc: PMC6468361
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Associazione Bianca Garavaglia
ID : A/18/01B
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