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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| Veröffentlicht in: | Blood Jg. 129; H. 2; S. 177 - 187 |
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| Sprache: | Englisch |
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12.01.2017
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| ISSN: | 1528-0020 |
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| Abstract | 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. |
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| AbstractList | 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. |
| Author | Harvey, Richard C Willman, Cheryl L Chen, I-Ming Li, Yong Tasian, Sarah K Teachey, David T Grupp, Stephan A Vincent, Tiffaney L Shen, Feng Perl, Alexander E Loh, Mignon L Hunger, Stephen P Carroll, Martin Ryan, Theresa |
| Author_xml | – sequence: 1 givenname: Sarah K surname: Tasian fullname: Tasian, Sarah K organization: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 2 givenname: David T surname: Teachey fullname: Teachey, David T organization: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 3 givenname: Yong surname: Li fullname: Li, Yong organization: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA – sequence: 4 givenname: Feng surname: Shen fullname: Shen, Feng organization: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA – sequence: 5 givenname: Richard C surname: Harvey fullname: Harvey, Richard C organization: Department of Pathology, University of New Mexico, Albuquerque, NM – sequence: 6 givenname: I-Ming surname: Chen fullname: Chen, I-Ming organization: Department of Pathology, University of New Mexico, Albuquerque, NM – sequence: 7 givenname: Theresa surname: Ryan fullname: Ryan, Theresa organization: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA – sequence: 8 givenname: Tiffaney L surname: Vincent fullname: Vincent, Tiffaney L organization: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA – sequence: 9 givenname: Cheryl L surname: Willman fullname: Willman, Cheryl L organization: Department of Pathology, University of New Mexico, Albuquerque, NM – sequence: 10 givenname: Alexander E surname: Perl fullname: Perl, Alexander E organization: Division of Hematology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and – sequence: 11 givenname: Stephen P surname: Hunger fullname: Hunger, Stephen P organization: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – sequence: 12 givenname: Mignon L surname: Loh fullname: Loh, Mignon L organization: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA – sequence: 13 givenname: Martin surname: Carroll fullname: Carroll, Martin organization: Division of Hematology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and – sequence: 14 givenname: Stephan A surname: Grupp fullname: Grupp, Stephan A organization: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27777238$$D View this record in MEDLINE/PubMed |
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| Snippet | Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or... |
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| SubjectTerms | 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 |
| Title | Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia |
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