Integrin-mediated drug resistance in multiple myeloma

Drug resistance remains a major obstacle to the treatment of many hematopoietic malignancies such as multiple myeloma. Although much research has been focused on acquired resistance phenotypes, we believe that de novo drug resistance mechanisms may be an important component in protecting cells from initial drug exposure. It is now realized that many of the biological processes associated with this disease, including cell survival, may come as a result of the direct interactions of malignant plasma cells with the bone marrow microenvironment. This review examines the role of cell adhesion to one bone marrow component, fibronectin (FN), and the impact it may have on response to cytotoxic drugs. We discuss the influence of the integrin VLA-4 (alpha4beta1) on cell adhesion mediated drug resistance (CAM-DR) as well as the effects of chronic drug exposure on integrin function. Data presented here demonstrates that drug selection can make a non-adherent cell line adherent to FN through inside-out integrin activation and consequently cause a decrease in sensitivity to drug. We also speculate on the possible mediators of this intrinsic mechanism of drug resistance which may, along with the integrins themselves, become promising therapeutic targets in cancer treatment.