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Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor

2010; Nature Portfolio; Volume: 16; Issue: 2 Linguagem: Inglês

10.1038/nm.2091

1546-170X

Matthew R. Janes, Jose J. Limon, Lomon So, Jing Chen, Raymond J. Lim, Melissa A Chavez, Collin Vu, Michael B. Lilly, Sharmila Mallya, S. Tiong Ong, Marina Konopleva, Michael Martin, Pingda Ren, Yi Liu, Christian Rommel, David A. Fruman,

Mast cells and histamine

The protein kinase mTOR is known to contribute to cancer development. However, existing drugs targeting mTOR, such as rapamycin, have not been very effective at inhibiting cancer cell survival and also have the unwanted side effect of immunosuppression. Studying preclinical models of leukemia driven by the BCR-ABL oncogene, Matthew Janes et al. now show that a new mTOR inhibitor—which unlike previous ones is an ATP competitive inhibitor that targets the active site of the enzyme—can overcome these drawbacks. Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. Unexpectedly, PP242 has much weaker effects than rapamycin on the proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase (PI3K), is more immunosuppressive than PP242. These findings establish that Ph+ transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.