Recent Insights into Therapy Resistance in Osteosarcoma

Abstract

Osteosarcoma, the most common bone malignancy of childhood, has been a challenge to treat and cure. Standard chemotherapy regimens work well for many patients, but there remain minimal options for patients with progressive or resistant disease, as clinical trials over recent decades have failed to significantly improve survival. A better understanding of therapy resistance is necessary to improve current treatments and design new strategies for future treatment options. In this review, we discuss known mechanisms and recent scientific advancements regarding osteosarcoma and its patterns of resistance against chemotherapy, radiation, and other newly-introduced therapeutics.

Keywords: autophagy; chemotherapy resistance; hypoxia; osteosarcoma; radiation resistance; tumor microenvironment.

Figure 1

The canonical Wnt/β-catenin pathway, the Hippo/YAP/TAZ pathway, and the PI3K/Akt pathway are each involved and have overlapping features that contribute to chemotherapy resistance and overall osteosarcoma progression. In the absence of Wnt, β-catenin and YAP/TAZ are bound to the Axin protein complex. YAP/TAZ recruits additional enzymes that ubiquitinate β-catenin and cause its degradation. Wnt activates the Frizzled (Fzd) and low-density lipoprotein receptor 5/6 (LRP5/6) coreceptors, which bind to disheveled (Dvl) and the Axin protein complex. This binding causes casein kinase 1α (CK1α) and glycogen synthase kinase 3β (GSK3β) to phosphorylate the cytoplasmic portion of LRP5/6 and further propagate Axin’s release of β-catenin and YAP/TAZ. β-catenin then translocates to the nucleus to activate genes participating in therapy resistance [25]. β-catenin expression is also decreased when lncRNAs HOTTIP is upregulated [37]. TRIM37 also activates the Wnt/β-catenin pathway [29]. Free YAP/TAZ participates in the Hippo pathway, which upon activation causes hyper-phosphorylation of YAP/TAZ and prevents nuclear translocation [30,31]. Additionally, the PI3K/Akt pathway also participates in chemoresistance [35,36]. MiR-22 suppresses PI3K expression [38], while miR-155 and miR-221 suppress PTEN [39,40], miR-214 activates Akt by promoting its phosphorylation [41], and miR-584 inhibits NFκB activity. MARK2 has also been shown to promote activation of the PI3K/Akt/NFκB pathway [35]. ARSR and TUG1 promote Akt upregulation and activation [42,43]. Created with BioRender.com.