Abstract
Despite advances in neoadjuvant chemotherapy, outcomes for patients with osteosarcoma resistant to first-line chemotherapy have been dismal for decades. There is thus an urgent need to develop novel targeted drugs to effectively treat refractory osteosarcoma. Dysregulation in the PI3K/AKT pathway has been observed during the development of osteosarcoma. Herein, we first evaluated p-AKT (Ser473) expression levels in osteosarcoma tissue using high-throughput tissue microarrays. Then, we demonstrated the role of pictilisib, a novel potent PI3K inhibitor, in osteosarcoma and related osteolysis. Functional studies of pictilisib in osteosarcoma cell lines and bone marrow-derived macrophages were performed in vitro. Patient-derived xenografts and orthotopic mouse models were used to assess the effects of pictilisib in vivo. The results showed that positive p-AKT expression levels after neoadjuvant chemotherapy were significantly associated with tumor cell necrosis rate. Pictilisib effectively inhibited the proliferation of osteosarcoma through G0/G1-S phase cell cycle arrest, and enhanced the sensitivity of osteosarcoma to doxorubicin, although it failed to induce cell apoptosis alone. In addition, pictilisib inhibited differentiation of osteoclasts and bone resorption in vitro and tumor-related osteolysis in vivo via inhibition of the PI3K/AKT/GSK3β and NF-κB pathways. Pictilisib combined with conventional chemotherapy drugs represents a potential treatment strategy to suppress tumor growth and bone destruction in p-AKT-positive patients.
Highlights
Osteosarcoma (OS) is the most frequent primary malignant bone tumor and occurs mainly in the young [1, 2]
Our results confirmed that p-AKT (Ser473) had a significant correlation with tumor cell necrosis rate (TCNR) after chemotherapy (c2 = 11.487, P = 0.002) (Figure 1D), that is, positive p-AKT after chemotherapy was considered to be a sign of poor response to chemotherapy (TCNR
The introduction of neoadjuvant chemotherapy in the 1970s led to a dramatic increase in overall survival rates from 20 to 50–70%, but many novel therapeutic approaches developed over the past 40 years have failed to achieve higher cure rates [3]
Summary
Osteosarcoma (OS) is the most frequent primary malignant bone tumor and occurs mainly in the young [1, 2]. The standard therapy for newly diagnosed OS consists of four to six cycles of neoadjuvant chemotherapy with cisplatin, doxorubicin (DOX), methotrexate, and ifosfamide after biopsy. With this combination of drugs, the 5-year survival rate in non-metastatic OS patients has increased to 50–70%. Activation of the PI3K/ AKT pathway has been observed in the majority of OS cell lines by detecting kinome and mRNA expression profiling [8]. Ji et al found that the expression of p-AKT (Ser473) was negatively correlated with tumor cell necrosis rate (TCNR) after chemotherapy [9]. The PI3K/AKT signaling pathway is a potential source of therapeutic targets
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