title: Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.
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.
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Sarah K
authors: SK
authors: Tasian
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: David T
authors: DT
authors: Teachey
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
authors: Yong
authors: Y
authors: Li
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
authors: Feng
authors: F
authors: Shen
authors: Department of Pathology, University of New Mexico, Albuquerque, NM.
authors: Richard C
authors: RC
authors: Harvey
authors: Department of Pathology, University of New Mexico, Albuquerque, NM.
authors: I-Ming
authors: IM
authors: Chen
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
authors: Theresa
authors: T
authors: Ryan
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
authors: Tiffaney L
authors: TL
authors: Vincent
authors: Department of Pathology, University of New Mexico, Albuquerque, NM.
authors: Cheryl L
authors: CL
authors: Willman
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Division of Hematology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and.
authors: Alexander E
authors: AE
authors: Perl
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Stephen P
authors: SP
authors: Hunger
authors: Division of Hematology/Oncology, University of California San Francisco Benioff Children's Hospital, and.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.
authors: Mignon L
authors: ML
authors: Loh
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Division of Hematology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and.
authors: Martin
authors: M
authors: Carroll
authors: Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Stephan A
authors: SA
authors: Grupp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D053612:Janus Kinases; D016315:Proto-Oncogene Proteins c-abl; D058570:TOR Serine-Threonine Kinases