Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor.
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.
Janes
Matthew R
MR
Department of Molecular Biology & Biochemistry, Institute for Immunology, University of California-Irvine, Irvine, California, USA.
Limon
Jose J
JJ
So
Lomon
L
Chen
Jing
J
Lim
Raymond J
RJ
Chavez
Melissa A
MA
Vu
Collin
C
Lilly
Michael B
MB
Mallya
Sharmila
S
Ong
S Tiong
ST
Konopleva
Marina
M
Martin
Michael B
MB
Ren
Pingda
P
Liu
Yi
Y
Rommel
Christian
C
Fruman
David A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D020123:Sirolimus