Collectively, we generated and characterized osteosarcoma SaOS-2 sublines exhibiting stable cross-resistance to a broad spectrum of chemotherapeutic agents (e.g., Dox, Vin, PTX) due to the increased activity of ABC-transporters and activation of DDR pathways involved in DSB DNA repair during the initial steps of the acquisition of drug resistance. The gene discussed is ABCG2; the disease is osteosarcoma.