WAY-262611 ET-743 binds to the minor groove of the DNA helix with sequence-specific binding preference for GC-rich triplets and subsequently forms covalent adducts with the N2-position of guanine. As a result, the minor groove is exposed and turned toward the major groove. When such binding occurs, DNA strands become cross-linked and cannot be replicated, resulting in cell death. The direction of DNA turning is a novel feature among DNA minor grooveinteractive agents, thus making ET-743 unique. Chondrosarcomas are a heterogeneous group of tumors of mesenchymal origin that PF-06463922 develop in bone or cartilage and display chondrocytic characteristics. These tumors respond poorly to conventional treatments such as chemotherapy and radiation, and prognosis is related to tumor grade and differentiation status. The sensitivity of sarcoma cells to ET-743 and PM00104 has led us and others to consider these compounds as interesting candidates for future treatment of chondrosarcoma. However, as with other chemotherapeutic agents, the propensity of tumor cells to develop resistance to ET-743 or PM00104 poses a significant challenge for using this drug over an extended period of time. The goal of this study is to explore the mechanisms of ET-743 or PM00104 resistance in chondrosarcoma. Results from several clinical trials suggest that ET-743 has antitumor activity against several cancer types, including soft tissue sarcomas, breast cancer, and ovarian cancer. Patients with advanced ovarian and breast cancer as well as bone or soft tissue sarcomas typically undergo several lines of anti-cancer regimens before ultimately succumbing to their disease. Multidrug resistance is thought to play an important role in the inevitable failure of tumors to respond to each successive line of chemotherapy. Therefore, understanding the patterns and mechanisms of crossresistance and finding ways to overcome it is an important goal. Several studies have studied the mechanisms of ET-743 drug resistance with different approaches. However, contradictory results have been published from various groups attempting to correlate resistance to different expression levels of RNAs and proteins in resistant cells.