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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.