Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

Academic Article

Abstract

  • T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner.
  • Published In

  • PLoS One  Journal
  • Keywords

  • Animals, Apoptosis, Cell Proliferation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Indazoles, Mice, Mice, Inbred C57BL, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Signal Transduction, Sulfonamides, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
  • Digital Object Identifier (doi)

    Pubmed Id

  • 28515670
  • Author List

  • Ksionda O; Mues M; Wandler AM; Donker L; Tenhagen M; Jun J; Ducker GS; Matlawska-Wasowska K; Shannon K; Shokat KM
  • Start Page

  • e0193849
  • Volume

  • 13
  • Issue

  • 5