Genetic predictors for drug resistance in soft tissue sarcoma: a review of publications in 2004

Abstract

Sarcomas are generally managed through a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Metastatic tumor cells frequently develop resistance to cytotoxic agents. Several molecular mechanisms of drug resistance have been uncovered recently. Among genes governing the apoptosis pathway, overexpression of the bcl2 family or mutations of p53 have recently been reported to be involved in drug resistance in sarcoma. The multidrug resistance genes are involved in the efflux of chemotherapeutic agents. Identification of members of this family of genes may predict resistance for developing new strategies. Several histologic subtypes of sarcomas have specific mechanisms of resistance. Methotrexate is one of the four active drugs for osteosarcoma and penetrates in tumor cell through specific carrier (reduced folate carrier) whose levels of expression or changes in amino acid sequence correlate to resistance to methotrexate. Specific molecular alteration defining nosological entities among sarcoma also correlates to drug resistance. Thirty percent of human sarcomas are characterized by specific translocations that may predict, for specific subtypes, survival and response to treatment. Finally, gastrointestinal tumors harbor specific activating mutations in KIT or PDGFRA genes, which are responsive to imatinib. Specific mutations of the KIT and PDGFRA genes have now repeatedly been found correlated to response or resistance to imatinib. The molecular alterations present in tumor cells predict influence sensitivity or resistance to chemotherapy. Ultimately, this may delineate specific therapeutic strategies for both cytotoxic and targeted therapies in sarcomas.