Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia.

Abstract

PURPOSE:

Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established.

EXPERIMENTAL DESIGN:

We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative.

RESULTS:

Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2.

CONCLUSIONS:

Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes.

• Authors: Susanne Badura, Tamara Tesanovic, Heike Pfeifer, Sylvia Wystub, Bart A Nijmeijer, Marcus Liebermann, J H Frederik Falkenburg, Martin Ruthardt, Oliver G Ottmann
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e80070 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24244612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
• 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one
• Aminopyridines
• Antineoplastic Agents
• Imidazoles
• Morpholines
• Multiprotein Complexes
• NVP-BKM120
• Naphthyridines
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Quinolines
• Ku 0063794
• Everolimus
• MTOR protein, human
• Fusion Proteins, bcr-abl
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• dactolisib
• Sirolimus

Topics

• Aminopyridines (pharmacology)
• Antineoplastic Agents (pharmacology)
• Drug Synergism
• Everolimus
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Imidazoles (pharmacology)
• Lymphocytes (drug effects, metabolism, pathology)
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Morpholines (pharmacology)
• Multiprotein Complexes (antagonists & inhibitors, genetics, metabolism)
• Naphthyridines (pharmacology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism, pathology)
• Primary Cell Culture
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Quinolines (pharmacology)
• Signal Transduction (drug effects)
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)