ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo

摘要: // Gang Yin 1 , 2, * Jin Fan 1, Wei Zhou Qingfeng Ding Jun Zhang Xuan Wu Pengyu Tang Hao Bowen Wan and Guoyong Department of Spine Surgery, The First Affiliated Hospital Nanjing Medical University, Nanjing, Jiangsu 210029, China 2 Orthopaedics, Changzhou Wujin to Changzhou, 213017, These authors have contributed equally this work Correspondence to: Yin, email: guoyong_yin@sina.com, drguoyongyin@163.com Keywords: osteosarcoma, mTOR, CZ415, ERK, molecular-targeted therapy Received: April 11, 2017      Accepted: 18, Published: May 30, 2017 ABSTRACT mTOR is a valuable oncotarget for osteosarcoma. anti-osteosarcoma activity by novel kinase inhibitor, was evaluated. We demonstrated that CZ415 potently inhibited survival proliferation known osteosarcoma cell lines (U2OS, MG-63 SaOs2), primary human cells. Further, provoked apoptosis disrupted cycle progression in treatment cells concurrently blocked mTORC1 mTORC2 activation. Intriguingly, ERK-MAPK activation could be major resistance factor CZ415. ERK inhibition (by MEK162/U0126) or knockdown targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced apoptosis. In vivo oral administration efficiently U2OS tumor growth mice. Its further potentiated with co-administration MEK162. Collectively, we demonstrate sensitizes vitro . tested as promising agent, alone combination inhibition.