Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia

BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), tr ansforms hematopoietic cells through both Ras-dependent and -independent me chanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to b lock mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribu te to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed pro liferation, and sensitized cells to apoptotic stimuli. Quantification of ac tivated guanosine triphosphate (GTP)-bound Ras protein and electrophoretic mobility shift assays for AP-1 DNA binding showed that Ras effector pathway s are inhibited by SCH66336. However, SCH66336 was more inhibitory than dom inant-negative Ras in assays of soft agar colony formation and cell prolife ration, suggesting activity against targets other than Ras. Cell cycle anal ysis of BCR/ABL-BaF3 cells treated with SCH66336 revealed G2/M blockade, co nsistent with recent reports that centromeric proteins that regulate the G2 /M checkpoint are critical farnesylated targets of FTI action. Mice injecte d intravenously with BCR/ABL-BaF3 cells developed acute leukemia and died w ithin 4 weeks with massive splenomegaly, elevated white blood cell counts, and anemia. In contrast, nearly all mice treated with SCH66336 survived and have remained disease-free for more than a year. Furthermore, SCH66336 sel ectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct fr om that of ABL tyrosine kinase inhibition, FTI SCH66336 shows promise for t he treatment of BCR/ABL-induced leukemia. (Blood, 2001;97: 1404-1412) (C) 2 001 by The American Society of Hematology.