Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336

The development of chronic myeloid leukemia (CML) is dependent on the deregulated tyrosine kinase of the oncoprotein BCR-ABL. ST1571 (Imatinib mesylate), an abl tyrosine kinase inhibitor, has proven remarkably effective for the treatment of CIVIL However, resistance to ST1571 because of enhanced expression or mutation of the BCR-ABL gene has been detected in patients. In the current study we show that the farnesyl transferase inhibitor (FTI) SCH66336 (Ionafarnib) inhibits the proliferation of ST1571-resistant BCR-ABL-positive cell lines and hematopoietic colony formation from peripheral blood samples of ST1571-resistant patients with CML Moreover, SCH66336 enhances ST1571-induced apoptosis in ST1571-sensitive cells and, inpatients with ST1571 resistance from gene amplification, cooperates with ST1571 to induce apoptosis. Our data provide a rationale for combination clinical trials of ST1571 and SCH66336 in CIVIL patients and suggest that combination therapy may be effective in patients with ST1571 resistance. (C) 2002 by The American Society of Hematology.