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

Sarah K. Tasian, David T. Teachey, Yong Li, Feng Shen, Richard C. Harvey, I-Ming Chen, Theresa Ryan, Tiffaney L. Vincent, Cheryl L. Willman, Alexander E. Perl, Stephen P. Hunger, Mignon L. Loh, Martin Carroll and Stephan A. Grupp

Key points

  • PI3K/mTOR inhibition potently inhibited leukemia proliferation and signal transduction in vivo in human Ph-like ALL xenograft models.

  • Combined PI3K/mTOR and JAK or ABL inhibition was superior to monotherapy in CRLF2/JAK-mutant and ABL/PDGFR-mutant Ph-like ALL models.

Abstract

Philadelphia chromosome-like B-cell lymphoblastic leukemia (BCR-ABL1-like or Ph-like ALL) is associated with activated JAK/STAT, SRC/ABL, and/or PI3K/Akt/mTOR signaling and poor clinical outcomes. Inhibitors of PI3K pathway signaling (PI3Ki) have been minimally investigated in Ph-like ALL to date. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or TORC1/TORC2 would decrease leukemia proliferation and abrogate aberrant kinase signaling. We further hypothesized that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated ten childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with four discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with the dual PI3K/mTOR inhibitor gedatolisib resulted in near-eradication of ALL in CRLF2/JAK-mutant models (n=7) with mean 92.2% (range 86.0-99.4%) reduction versus vehicle controls (p<0.0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/PDGFR-mutant models (n=3) with mean 66.9% (range 42.0-87.6%) reduction versus vehicle (p<0.0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (p<0.001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (p<0.001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo, and anti-leukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in patients with Ph-like ALL are indicated.

  • Submitted May 13, 2016.
  • Accepted October 17, 2016.