Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.
Olga KsiondaMarsilius MuesAnica M WandlerLisa DonkerMilou TenhagenJesse JunGregory S DuckerKsenia Matlawska-WasowskaKevin ShannonKevan M ShokatJeroen P RoosePublished in: PloS one (2018)
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.
Keyphrases
- pi k akt
- signaling pathway
- wild type
- combination therapy
- cell proliferation
- flow cytometry
- acute lymphoblastic leukemia
- single cell
- small molecule
- cell cycle arrest
- genome wide
- papillary thyroid
- cancer therapy
- end stage renal disease
- cell therapy
- endothelial cells
- magnetic resonance
- squamous cell
- randomized controlled trial
- magnetic resonance imaging
- mesenchymal stem cells
- immune response
- skeletal muscle
- transcription factor
- acute myeloid leukemia
- anti inflammatory
- bone marrow
- squamous cell carcinoma
- gene expression
- oxidative stress
- stem cells
- drug delivery
- single molecule
- young adults
- inflammatory response
- high fat diet induced
- toll like receptor
- nuclear factor
- real time pcr
- high glucose
- cell death
- pluripotent stem cells