Mechanisms of Resistance to Conventional Therapies for Osteosarcoma

Abstract

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.

Keywords: chemotherapy circumvent; chemotherapy resistance; osteosarcoma.

Figure 1

Some molecular mechanisms leading to the decrease of intracellular drug accumulation in osteosarcoma (OS) resistant tumor cells to conventional therapies. Sequence alterations of reduced folate carriers (RFC) lead to an impaired methotrexate (MTX) transport through the membrane cell, thereby reducing the accumulation of MTX inside the cell (in blue). Overexpression of members of ATP-binding cassette (ABC) family such as multidrug resistance protein 1 (MDR1) increases cisplatin (CDP,) doxorubicin (DOX), and methotrexate (MTX) efflux and elimination leading to chemoresistance (in brown). Overexpression or decrease expression of MTX/DOX-target enzymes lead to OS resistance. Chemotherapeutic agents, such as MTX or DOX, interact and inhibit target enzymes such as dihydrofolate reductase (DHFR). DHFR inhibition limits conversion of dihydrofolate (DHF) to tetrahydrofolate (THF), leading to a decrease in DNA synthesis and cell growth. DHFR overexpression in OS-resistant cells decreases MTX and DOX cytotoxicity leading to the emergence of resistance. Topoisomerase II (TopoII), an enzyme responsible for the topological state of DNA and, therefore, cell viability. DOX stabilize topoisomeraseII/DNA complex leading to cell death. Decrease expression of topoisomerase II decreases cytotoxicity of DOX and promotes the emergence of resistance (in green).

Figure 2

Some examples of signaling pathways involved in OS resistant tumor cells to conventional treatment. Cell surface-receptors, such as tyrosine kinase receptors (RTKs), are disturbed in resistant cells to chemotherapy. Over-expression and phosphorylation of RTKs activate signaling pathways such as mitogen-activated protein kinases (MAPK) or phosphoinositol 3-kinase (PI3K)-protein kinase signaling pathway. Activation of MAPK and/or PI3K leads to proliferation and survival, respectively. Several WNT ligands (WNT 10b) and receptors (lipoprotein receptor-related protein 5—LRP5) and β-catenin are over-expressed and activate the WNT/β-catenin pathway leading to β-catenin overexpression. β-catenin is able to repress syndecan-2 leading to inhibition of apoptosis and chemosensitivity.