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.

doi:10.3390/cancers12061519

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
Autori:	Chiabotto G. Grignani G. Todorovic M. Martin V. Centomo M. L. Prola E. Giordano G. Merlini A. Miglio U. Berrino E. NAPIONE, LUCIA Isella C. Capozzi F. Basirico M. Marsero C. Gerardi I. Venesio T. Sangiolo D. Aglietta M. D'ambrosio L. Pignochino Y. mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2020
Rivista:	CANCERS
Digital Object Identifier (DOI):	http://dx.doi.org/10.3390/cancers12061519
Appare nelle tipologie:	1.1 Articolo in rivista

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