nce the available anti BCR ABL1 TKIs seem unable to eliminate dormant cells, the question is how to devise alternative biological strategies to eradicate them. Recent studies from different groups have provided encouraging potential therapeutic approaches. Protein phosphatase 2A activation PP2A is a tumor suppressor whose activity is inhibited in Philadelphia BMS-554417 IGF-1R inhibitor positive leukemias but not in normal hematopoietic stem/progenitor cells.3 Drugs such as FTY720 and its non phosphorylatable derivative4 re activate PP2A, thereby limiting the adverse effect that other types of drugs might exert on normal cells. FTY720, an immunosuppressive synthetic sphingosine analog,5 shows anti leukemic activity on CD34 cells from TKI sensitive and TKI resistant CML progenitors.
6 FTY720 acts as an anti leukemic agent in its non phosphorylated form without exerting toxicity on normal myelopoiesis.6 9 The question arises whether BCR ABL1 is necessary for OSU-03012 PDK-1 inhibitor this drug to work. In CML progenitors, FTY720 induces apoptosis because of the ability of active PP2A to simultaneously impair BCR ABL1 activity/expression. 6 Recent evidence suggests that FTY720 also targets other kinases through PP2A.8 In primitive CML cells, the apoptotic effect of FTY720 might not require BCR ABL1 activity7 which, as reported, is not essential for their survival. 10 Indeed, it seems that alternative signaling pathways which require the expression of BCR ABL1 for their activation and/or maintenance are necessary for the effect of FTY720 in the most primitive CML cells.
Overall, FTY720 can kill primitive and mature progenitor cells without showing any type of toxicity other than its possible immunosuppressive activity. Because FTY720 has the property of acting on different oncogene driven pathways while preserving normal cells, it is not surprising that it is active in different leukemias.9,11 Farnesyl transferase inhibition Copland, Holyoake and colleagues reported that BMS215662, a farnesyl transferase inhibitor, showed preferential cytotoxicity against non proliferative cells, different from most drugs. It eradicates Ph primitive long term culture initiating cells, either alone or in combination with imatinib or dasatinib.12 In vivo, it has little effect on the engraftment of K562 cells in mice when used as a single agent, but there is virtually no K562 tumor formation when it is combined with dasatinib.
It selectively increases caspase 3, thus causing apoptosis in CML CD34CD38 cells but in not their normal counterparts. The mechanism of apoptosis seems to be triggered by aberrant phosphorylation of CDK2 in CML cells which, in its turn, leads to a conformational change in the anti apoptotic protein BAX, significant release of cytochrome c from the mitochondria, mitochondria swelling, and eventual activation of the caspase pathway. Autophagy inhibition CML cells which survive TKI treatment show reduced size and significant increase in cytoplasmic vacuoles, an effect similar to growth factor deprivation.13 This is the phenotype of cells undergoing autophagy, a biological response to nutrient shortage. Once the autophagy process starts, the enzyme LC3 is converted from a cytosolic to a membrane bound form. Treatment of CML stem cells with dasatinib causes such LC3 conversion and increase of autophagy. This observation provided the rationale for combining a TKI, which kills only more mature BCR A