Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia

Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-...

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Bibliographic Details
Published in:	Blood Vol. 129; no. 2; pp. 177 - 187
Main Authors:	Tasian, Sarah K, Teachey, David T, Li, Yong, Shen, Feng, Harvey, Richard C, Chen, I-Ming, Ryan, Theresa, Vincent, Tiffaney L, Willman, Cheryl L, Perl, Alexander E, Hunger, Stephen P, Loh, Mignon L, Carroll, Martin, Grupp, Stephan A
Format:	Journal Article
Language:	English
Published:	United States 12.01.2017
Subjects:	Animals Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Humans Janus Kinases - antagonists & inhibitors Mice Phosphoinositide-3 Kinase Inhibitors Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-abl - antagonists & inhibitors Random Allocation Signal Transduction - drug effects TOR Serine-Threonine Kinases - antagonists & inhibitors Xenograft Model Antitumor Assays
ISSN:	1528-0020
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Summary:	Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1528-0020
DOI:	10.1182/blood-2016-05-707653