Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells

SIMPLE SUMMARY: Osteosarcoma (OS) is a common malignant bone tumor in adolescents whose survival rates have not improved over the past few decades. At present, there is a lack of effective molecule-targeted therapy. Abnormal activation of c-Met is often detected in patients with OS, and c-Met inhibitors are considered to have tumor suppressive potential. However, OS is prone to acquire resistance to c-Met inhibitor, and the mechanisms of drug resistance are poorly understood. The goal of this study is to explore the mechanism of resistance to c-Met-targeted inhibitors. Our results demonstrate that the neovascular microenvironment contributes to the resistance of OS to c-Met-targeted therapy. Simultaneous targeting of c-Met and VEGFR2 can effectively overcome drug resistance. ABSTRACT: Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents characterized by drug resistance and poor prognosis. As one of the key oncogenes, c-Met is recognized as a promising therapeutic target for OS. In this report, we show that c-Met inhibitor PF02341066 specifically killed OS cells with highly phosphorylated c-Met in vitro. However, the inhibitory effect of PF02341066 was abrogated in vivo due to interference from the vascular niche. OS cells adjacent to microvessels or forming vascular mimicry suppressed c-Met expression and phosphorylation. Moreover, VEGFR2 was activated in OS cells and associated with acquired drug resistance. Dual targeting of c-Met and VEGFR2 could effectively shrink the tumor size in a xenograft model. c-Met-targeted therapy combined with VEGFR2 inhibition might be beneficial to achieve an ideal therapeutic effect in OS patients. Together, our results confirm the pivotal role of tumor heterogeneity and the microenvironment in drug response and reveal the molecular mechanism underlying acquired drug resistance to c-Met-targeted therapy.