PMID- 32531992
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 6
DP  - 2020 Jun 10
TI  - Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: 
      Preclinical Activity and Molecular Insights.
LID - 10.3390/cancers12061519 [doi]
LID - 1519
AB  - 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.
FAU - Chiabotto, Giulia
AU  - Chiabotto G
AUID- ORCID: 0000-0002-1420-3517
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Grignani, Giovanni
AU  - Grignani G
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Todorovic, Maja
AU  - Todorovic M
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Martin, Valentina
AU  - Martin V
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Centomo, Maria Laura
AU  - Centomo ML
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Prola, Elisa
AU  - Prola E
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Giordano, Giorgia
AU  - Giordano G
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Merlini, Alessandra
AU  - Merlini A
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Miglio, Umberto
AU  - Miglio U
AD  - Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), 
      Italy.
FAU - Berrino, Enrico
AU  - Berrino E
AUID- ORCID: 0000-0001-6728-5619
AD  - Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), 
      Italy.
AD  - Department of Medical Sciences, University of Torino, 10100 Torino, Italy.
FAU - Napione, Lucia
AU  - Napione L
AUID- ORCID: 0000-0003-2648-1466
AD  - Laboratory of Vascular Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 
      Candiolo (TO), Italy.
AD  - Department of Applied Science and Technology, Politecnico di Torino, 10060 
      Torino, Italy.
FAU - Isella, Claudio
AU  - Isella C
AD  - Laboratory of Oncogenomics, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo 
      (TO), Italy.
FAU - Capozzi, Federica
AU  - Capozzi F
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Basirico, Marco
AU  - Basirico M
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
FAU - Marsero, Cristina
AU  - Marsero C
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Gerardi, Ilaria
AU  - Gerardi I
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Venesio, Tiziana
AU  - Venesio T
AD  - Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), 
      Italy.
FAU - Sangiolo, Dario
AU  - Sangiolo D
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Aglietta, Massimo
AU  - Aglietta M
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - D'Ambrosio, Lorenzo
AU  - D'Ambrosio L
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
FAU - Pignochino, Ymera
AU  - Pignochino Y
AUID- ORCID: 0000-0001-5073-8618
AD  - Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Str. Prov. 
      142 km 3.95, 10060 Candiolo (TO), Italy.
AD  - Department of Oncology, University of Torino, 10124 Torino, Italy.
LA  - eng
GR  - IG 17226/Associazione Italiana per la Ricerca sul Cancro/
GR  - CRT RF = 2016-0917/Fondazione per la ricerca sui tumori dell'apparato 
      muscoloscheletrico e rari ONLUS/
PT  - Journal Article
DEP - 20200610
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7352822
OTO - NOTNLM
OT  - EphA2
OT  - IL-7R
OT  - MEK6
OT  - osteosarcoma
OT  - pazopanib
OT  - trametinib
OT  - tyrosine-kinase inhibitors
COIS- G.G. (Giovanni Grignani) has received fees for consulting and advisory board 
      roles from PharmaMar, Lilly, Novartis, Bayer, and Eisai. L.D. received travel 
      expenses from PharmaMar and Lilly. M.A. has received fees for consulting or 
      advisory board roles from Bristol-Myers Squibb, Merck, and Roche. All other 
      authors declare no competing interest.
EDAT- 2020/06/14 06:00
MHDA- 2020/06/14 06:01
PMCR- 2020/06/10
CRDT- 2020/06/14 06:00
PHST- 2020/05/19 00:00 [received]
PHST- 2020/06/08 00:00 [revised]
PHST- 2020/06/09 00:00 [accepted]
PHST- 2020/06/14 06:00 [entrez]
PHST- 2020/06/14 06:00 [pubmed]
PHST- 2020/06/14 06:01 [medline]
PHST- 2020/06/10 00:00 [pmc-release]
AID - cancers12061519 [pii]
AID - cancers-12-01519 [pii]
AID - 10.3390/cancers12061519 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Jun 10;12(6):1519. doi: 10.3390/cancers12061519.