Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights
Open Access
- 10 June 2020
- Vol. 12 (6), 1519
- https://doi.org/10.3390/cancers12061519
Abstract
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.Keywords
Funding Information
- Associazione Italiana per la Ricerca sul Cancro (IG 17226)
This publication has 58 references indexed in Scilit:
- Response to Pazopanib in Patients With Relapsed OsteosarcomaJournal of Pediatric Hematology/Oncology, 2020
- Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic OsteosarcomaJournal of Clinical Oncology, 2019
- Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcomaInternational Journal of Cancer, 2019
- Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 studyThe Lancet Oncology, 2018
- Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone MicroenvironmentScientific Reports, 2018
- Translational biology of osteosarcomaNature Reviews Cancer, 2014
- Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: Current hurdles and future perspectivesBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014
- A Review of Targeted Therapies Evaluated by the Pediatric Preclinical Testing Program for OsteosarcomaFrontiers in Oncology, 2013
- Multiple receptor tyrosine kinases promote the in vitro phenotype of metastatic human osteosarcoma cell linesOncogenesis, 2012
- MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future DirectionsSarcoma, 2012