Current progress and open challenges for applying tyrosine kinase inhibitors in osteosarcoma

Abstract

Osteosarcoma (OS) is a mesenchymal-origin tumor that constitutes the most common primary malignant bone tumor. The survival rate of the patients has significantly improved since the introduction of neoadjuvant chemotherapy and extensive resection, but it has stagnated in recent 40 years. Tyrosine kinase inhibitors (TKIs) have played a key part in the treatment of malignant tumors. In advanced OS, TKIs including anlotinib, apatinib, sorafenib, etc. have significantly improved the progression-free survival of patients, while the overall survival remains unchanged. The main reason is the rapid and inevitable progress of acquired drug resistance of OS. However, as the application of TKIs in OS and other tumors is still in the exploratory phase, its drug resistance mechanism and corresponding solutions are rarely reported. Hence, in this review, we summarize knowledge of the applications of TKIs, the mechanism of TKIs resistance, and the attempts to overcome TKIs resistance in OS, which are the three potentially novel insights of TKIs in OS. Because most evidence is derived from studies using animal and cell models, we also reviewed clinical trials and related bioinformatics data available in public databases, which partially improved our understanding of TKIs applications.

Imaging Assessment of the Efficacy of Chemotherapy in Primary Malignant Bone Tumors: Recent Advances in Qualitative and Quantitative Magnetic Resonance Imaging and Radiomics

“…Imatinib is listed as an effective chemotherapy medication for recurrent chordomas, while pembrolizumab was confirmed to be effective in improving the tissue tumor mutational burden of patients with UPS 11 . Targeted therapeutic research on OS mostly focuses on Tyrosine kinase inhibitors, such as anlotinib, apatinib, sorafenib, and regorafenib, because they can significantly improve the progression‐free survival in patients with advanced OS 12–14 . Immunotherapy is now attracting increasing attention in the scientific literature; however, the results of the SARC028 trials revealed that patients with malignant bone tumors showed suboptimal response to immune checkpoint inhibitors 15 …”

“…11 Targeted therapeutic research on OS mostly focuses on Tyrosine kinase inhibitors, such as anlotinib, apatinib, sorafenib, and regorafenib, because they can significantly improve the progression-free survival in patients with advanced OS. [12][13][14] Immunotherapy is now attracting increasing attention in the scientific literature; however, the results of the SARC028 trials revealed that patients with malignant bone tumors showed suboptimal response to immune checkpoint inhibitors. 15 CURRENT FOLLOW-UP GUIDELINES.…”

Relationship between Osteosarcoma Therapy and Tumorigenesis, Metastasis, Immune Evasion, and Chemoresistance

“…Chemoresistance therapies are always accompanied by treatments for severe off-target effects to restore therapeutic compliance [161]. The acquired nature of chemoresistance in cancer cells will minimise the cytotoxic agent's delivery proportionally to the chemotherapeutic treatment duration [162].…”

BMS-794833 reduces anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway

“…However, the development of drug resistance and the genetic heterogeneity of osteosarcoma may limit the effectiveness and applicability of anlotinib [6] , [19] . Combining anlotinib with other VEGFR-targeting drugs, such as sorafenib, is a potential approach to amplifying its therapeutic effects against osteosarcoma [20] , [21] . In addition, obstructing multiple tumor angiogenesis-associated pathways simultaneously may synergistically suppress tumor growth [22] .…”