Abstract
Simple SummaryOsteosarcoma (OS), the most common primary bone tumor, mainly affects children and adolescents. Unfortunately, in some cases, the absence of response to chemotherapy agents is observed, leading to metastases development and death of the patient. Resistance is one of the biological processes at the origin of therapeutic failure. In order to improve the therapeutic management of patients, it is necessary to identify and better understand the mechanisms underlying resistance. Here, we summarize molecular mechanisms of OS resistance to conventional chemotherapy and list some strategies that overcome resistance.Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development.
Highlights
Osteosarcoma (OS) is the most common primary bone tumor representing approximately 30% of bone sarcomas, and mainly affecting children and adolescents with an 18-years incidence peak [1]
This can be mediated by GSTP1 overexpression and by regulation of signaling pathways such as the mitogen-activated protein kinase (MAPK) or c-Jun N-terminal kinase (JNK) pathways
A proteomic investigation showed that NBDHEX dissociated the GSTP1-tumor necrosis factor receptor-associated factor (TRAF) 2 complex, activating JNK and p38 and leading to DNA damage and apoptosis [124]
Summary
Osteosarcoma (OS) is the most common primary bone tumor representing approximately 30% of bone sarcomas, and mainly affecting children and adolescents with an 18-years incidence peak [1]. Tumor resistant cells exhibiting pre-existing genetic mutations or activation of different signaling pathways would be able to proliferate despite the presence of chemotherapy agents. Tumor cells will develop mechanisms such as activation of proto-oncogene, mutations, or altered expression levels of transport proteins or drug targets, and changes in the tumor microenvironment (TME) [24]. These adaptations subsequently allow tumor cells to resist chemotherapy. It is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to elaborate new strategies and to adapt treatments for patients, improving the survival rate. Tumor cells can (1) establish inefficient transport by reducing the number of carriers on their surface [28], (2) initiate drug elimination by increasing drug efflux [29], (3) induce alterations in structure or expression of target enzyme [30] (Figure 1)
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