Abstract
Despite recent improvements in the therapeutic management of osteosarcoma (OS), the ongoing challenges in overcoming resistance to tyrosine kinase inhibitors (TKIs) warrant new strategies to improve overall patient survival. In this study, we established four anlotinib-resistant OS cell lines and demonstrated that the mechanism of anlotinib resistance is due to the loss of PTEN and reactivation of the MAPK pathway. Reduced PTEN expression was also observed in tumor samples from patients with OS and lung metastasis. We investigated the effects of an orally active PI3K inhibitor, either alone or in combination with anlotinib, on the progression of resistant cells and a xenograft nude mouse model. Notably, PI3K inhibitor suppressed anlotinib-resistant OS cell proliferation, migration, invasion, and cytoskeleton formation, and induced apoptosis. Combined treatment with anlotinib augmented these effects by restoring PTEN expression and decreasing MAPK and PI3K/AKT/mTOR signaling. PI3K inhibitors could reverse anlotinib resistance in OS, limiting OS cell development in combination with anlotinib. Our findings rationalize further studies on the applications of PI3K inhibitors that can be clinically used in anlotinib-refractory OS management.