Potent Efficacy of Combined PI3K/mTOR and JAK or SRC/ABL Inhibition in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

• Published in: Blood 2015-12, Vol.126 (23), p.798-798
• Main Authors: Tasian, Sarah K, Li, Yong, Shen, Feng, Ryan, Theresa, Vincent, Tiffaney L, Teachey, David T, Maude, Shannon L, Harvey, Richard C, Chen, I-Ming L, Willman, Cheryl L, Perl, Alexander E., Hunger, Stephen P, Loh, Mignon L., Carroll, Martin, Grupp, Stephan A.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.798.798

Background. Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with genomic alterations that activate JAK/STAT and PI3K/Akt/mTOR signal transduction and with poor clinical outcomes. Therapeutic disruption of PI3K pathway signaling in Ph-like ALL has been minimally investigated to date, however. We hypothesized that PI3K isoform-selective or dual PI3K pathway protein inhibition would robustly inhibit Ph-like ALL proliferation in vivoand abrogate aberrant signaling. Methods. NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were engrafted with primary CRLF2/JAK-mutant or ABL/PDGFR-mutant Ph-like ALL specimens (Table 1) and treated with inhibitors of PI3K? (BYL719), PI3K? (idelalisib), PI3K/mTOR (gedatolisib), TORC1/TORC2 (AZD2014) or with vehicle. Treated patient-derived xenograft (PDX) models were assessed for pharmacodynamic inhibition of signal transduction phosphoproteins at 72 hours by phosphoflow cytometry and for residual ALL in murine spleens after 3-4 weeks of inhibitor or vehicle treatment by quantitative flow cytometry. Subsequent studies tested the efficacy of gedatolisib with the JAK1/2 inhibitor ruxolitinib (CRLF2/JAK-mutant models) or gedatolisib with the SRC/ABL inhibitor dasatinib (ABL/PDGFR-mutant models). Table 1Genomic characteristics of Ph-like ALL specimens utilized for PDX studies.USIDisease statusCRLF2/JAK alterationsABL/PDGFR alterationsPALTWSDIGH@-CRLF2*PAMDKSDIGH@-CRLF2, JAK2R683GPAMDRMDIGH@-CRLF2,JAK2GPinsR683ALL121RIGH@-CRLF2, JAK2R683GALL4364RP2RY8-CRLF2, JAK2R683GPAKMVDDJAK1S646FPAKYEPDBCR-JAK2PAKKCADEBF1-PDGFRBPAKVKKDNUP214-ABL1PANSFDDETV6-ABL1USI = unique specimen identifier. D = de novo, R = relapse. * non-Ph-like by prediction analysis of microarrays. Results. All tested PDX models demonstrated inhibition of leukemia proliferation and abrogation of activated signaling with PI3K pathway inhibition. Gedatolisib treatment resulted in near-eradication of leukemia in CRLF2/JAK-mutant models (n=7) with mean 92.2% (range 86.0-99.4%) leukemia reduction vs vehicle treatment (p