Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation

Integrin-mediated cellular adhesion to extracellular matrix (ECM) component s is an important determinant of chemotherapeutic response of human myeloma cells. Here, we demonstrate that when K562 chronic myelogenous leukemia (C ML) cells are adhered to fibronectin (FN), they become resistant Ito apopto sis induced by the BCR/ABL inhibitors AG957 and STI-571, as well as DNA dam aging agents and gamma -irradiation. This phenomenon, termed cell adhesion- mediated drug resistance (CAM-DR), was induced by adhesion through the alph a5 beta1 (VLA-5) integrin. Phosphotyrosine analysis demonstrates that anti- apoptotic signaling through integrins in K562 cells is independent of the t yrosine kinases activated by BCR/ABL, with the possible exception of an unk nown 80 kDa protein. Cytoprotection of FN-adhered CML cells indicates that tumor-ECM interactions may be critical for the emergence of drug-resistant tumor populations and treatment failure in this disease. Antagonists of bet a1 integrin-mediated adhesion or corresponding signal transduction elements may sensitize CML cells to chemotherapy and prevent resistance to the nove l BCR/ABL kinase inhibitors being used for the treatment of this disease.