The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL).
Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting.
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Mohiuddin
M
Gazi
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Sausan A
SA
Moharram
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Alissa
A
Marhäll
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden. Electronic address: kazi.uddin@med.lu.se.
Julhash U
JU
Kazi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D060066:Protein Interaction Maps; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; C549060:gedatolisib; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases
Gedatolisib; Leukemia; PF 05212384; PI3K/mTOR; T-ALL