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

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 wit

SUBMITTER: Tang W 

PROVIDER: S-EPMC9776923 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature