ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo
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Gang Yin1,2,*, Jin Fan1,*, Wei Zhou1, Qingfeng Ding1, Jun Zhang1, Xuan Wu1, Pengyu Tang1, Hao Zhou1, Bowen Wan1 and Guoyong Yin1
1Department of Spine Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
2Department of Orthopaedics, Changzhou Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213017, China
*These authors have contributed equally to this work
Keywords: osteosarcoma, mTOR, CZ415, ERK, molecular-targeted therapy
Received: April 11, 2017 Accepted: April 18, 2017 Published: May 30, 2017
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415. ERK inhibition (by MEK162/U0126) or knockdown (by targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced osteosarcoma cell apoptosis. In vivo, CZ415 oral administration efficiently inhibited U2OS tumor growth in mice. Its activity was further potentiated with co-administration of MEK162. Collectively, we demonstrate that ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo. CZ415 could be further tested as a promising anti-osteosarcoma agent, alone or in combination of ERK inhibition.
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