Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights.
EphA2
IL-7R
MEK6
osteosarcoma
pazopanib
trametinib
tyrosine-kinase inhibitors
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
10 Jun 2020
10 Jun 2020
Historique:
received:
19
05
2020
revised:
08
06
2020
accepted:
09
06
2020
entrez:
14
6
2020
pubmed:
14
6
2020
medline:
14
6
2020
Statut:
epublish
Résumé
Receptor tyrosine kinases (RTKs) inhibitors' activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism.
Identifiants
pubmed: 32531992
pii: cancers12061519
doi: 10.3390/cancers12061519
pmc: PMC7352822
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 17226
Organisme : Fondazione per la ricerca sui tumori dell'apparato muscoloscheletrico e rari ONLUS
ID : CRT RF = 2016-0917
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