An overview of resistance to chemotherapy in osteosarcoma and future perspectives

Abstract

Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

Keywords: Osteosarcoma; cell cycle; therapy resistance; tumoral extracellular microenvironment; tyrosine kinase inhibitor.

Figure 1

Reduced intracellular drug accumulation. (A) Decreased expression of the reduced folate transporter (RFC) or decreasing transporter function promotes methotrexate resistance. (B) Overexpression of dihydrofolate reductase (DHFR) responsible for the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) or alterations in the binding affinity of DHFR for methotrexate (MTX) are related with MTX resistance. (C) Decreased expression or mutation of topoisomerase II (Topo II) is associated with doxorubicin (DOX) resistance. (D) High levels of excision repair cross-complement protein 1 (ERCC1) proteins are related to cisplatin resistance. (E) Increased expression of multidrug resistance gene encoding the ATP-binding cassette (ABC) family leads to increased drug efflux and decreased intracellular drug accumulation increasing resistance to DOX and MTX.

Figure 2

Role of Family HER Pathway in osteosarcoma chemotherapy resistance. (A) Cisplatin resistance is associated with HER2 overexpression, PI3K/AKT activation and promotion p21 nuclear exclusion, favoring cell cycle arrest and proliferation. (B) Anti-EGFR therapy such as cetuximab and gefitinib sensitized osteosarcoma cells to DOX and MTX. (C) Afatinib a pan-HER Family inhibitor have an inhibition effect in osteosarcoma cell proliferation, migration an invasion. (D) Trastuzumab deruxtecan is an antibody-drug conjugated composed by anti-HER2 humanized monoclonal antibody and a topoisomerase I inhibitor as cytotoxic drug, that is now been tasted in clinical trials. AKT: Protein kinase B; DOX: doxorubicin; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; HER: human epidermal growth factor; MTX: methotrexate; PI3K/AKT: phosphoinositide 3-kinase.

Figure 3

Angiogenesis and osteosarcoma microenvironment. (A) Mesenchymal stem cells (MSCs) produce IL-6 and STAT3 pathway activation promoting cisplatin and DOX resistance. (B) Macrophages promotes angiogenesis by VEGFA production in osteosarcoma. (C) VEGFA ligand binds to VEGFR activating angiogenesis pathway, throw PI3K/AKT/mTOR or Ras. Some anti-angiogenesis tyrosine kinase inhibitors alone or in combination with mTOR inhibitors are approved in second line in osteosarcoma. (D) Integrin pathway actives SRC and FAK promoting angiogenesis and apoptosis inhibition. (E) Chemokine (C-C motif) ligand 3 (CCL3) binding to G-protein coupled C-C chemokine receptor 5(CCR5) promoting VEGFA expression by downregulation of miR-374b, activation of JNK/ERK/p38 and hypoxia-inducible factor (HIF) in human osteosarcoma cells. (F) The canonical Wnt/β- catenin pathway contributes to chemotherapy resistance and osteosarcoma progression. WNT actives the Frizzled (FZD) and low-density lipoprotein receptor 5/6 (LRP5/6) binding disheveled (DVL) and Axin protein complex release of β-catenin and lead the translocation of β-catenin to the nucleus to activates genes active in chemoresistance. (G) Endostatin inhibit the activity of integrin, VEGFR and WNT pathways. AKT: Protein kinase B; CCD1: CyclinD1; DOX: doxorubicin; DNA-PK: DNA-dependent protein kinase, ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; gp130: glycoprotein 130; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; IL-: interleukine-6; IL-6R: IL-6 receptor; JAK: Janus Kinase; JNK: JUN N-terminal kinase; MARK2: microtubule affinity-regulating kinase 2; MYC: myc proto-oncogene; NF-κB: nuclear factor-κB; SRC: SRC protein kinase; STAT3: signal transducer and activator of transcription 3; VEGF: vascular epidermal growth factor; VEGFR: vascular epidermal growth factor receptor.