Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Abstract

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40-50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.

Keywords: biomarker; drug resistance; osteosarcoma; personalized medicine.

Figure 1

Examples of sponging activity of lncRNAs with impact in osteosarcoma drug resistance. Through sponging activity, lncRNAs can regulate mRNA expression by competitively binding complementary miRNAs and, consequently, opposing their interaction with target mRNAs. Figure shows some lncRNAs that are overexpressed in osteosarcoma cells and negatively modulate the expression of target genes by sponging their regulatory miRNAs.

Figure 2

Involvement of osteosarcoma cancer stem cells in drug resistance. Osteosarcoma cancer stem cells (OS CSCs) represent a relatively small subpopulation in the tumoral bulk, characterized by high expression of stemness-related transcription factors (such as Sox2, Oct3/4, Nanog and Klf4). These characteristics promote self-renewal capability and enhanced multipotency, which enable OS CSCs to persist and to generate neoplastic cells as well, replenishing the tumoral bulk, i.e., following chemotherapy or surgical interventions. Nonetheless, the most critical feature of OS CSCs is enhanced drug resistance towards the main anti-neoplastic agents involved in high-grade osteosarcoma treatment, as a consequence of different mechanisms (the most relevant of which are shown in this Figure). Such chemoresistance may be enforced by aberrant miRNA expression and by alteration of different signaling pathways mainly induced by stimuli of the tumoral microenvironment.

Figure 3

New candidate agents to overcome drug resistance in HGOS. The chemical structures of new drugs discussed in chapter 3. Only molecules which are not protected by copyright are shown.