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.
Pazopanib and trametinib as a synergistic strategy against osteosarcoma: Preclinical activity and molecular insights / Chiabotto, G.; Grignani, G.; Todorovic, M.; Martin, V.; Centomo, M. L.; Prola, E.; Giordano, G.; Merlini, A.; Miglio, U.; Berrino, E.; Napione, L.; Isella, C.; Capozzi, F.; Basirico, M.; Marsero, C.; Gerardi, I.; Venesio, T.; Sangiolo, D.; Aglietta, M.; D'ambrosio, L.; Pignochino, Y.. - In: CANCERS. - ISSN 2072-6694. - 12:6(2020), pp. 1-21.
|Titolo:||Pazopanib and trametinib as a synergistic strategy against osteosarcoma: Preclinical activity and molecular insights|
|Data di pubblicazione:||2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/cancers12061519|
|Appare nelle tipologie:||1.1 Articolo in rivista|