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.
Highlights
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer characterized by abnormal growth and proliferation of early T cell progenitors
We observed widespread phosphorylation of Akt in T-ALL cells with either Ras guanine nucleotide releasing protein 1 (RasGRP1) overexpression or an oncogenic Kras mutation and in human Jurkat and MOLT-3 T-ALL cell lines, yet with heterogeneous intensity and different patterns of activation either at baseline and/or following cytokine stimulation (Fig 1A– 1C). These results expand on previous findings in human T-ALL cell lines [6, 17, 19,20,21] and further motivated us to perform a comprehensive analysis of phosphoinositide 3-kinase (PI3K)-Akt signaling in T-ALL
We find that the PI3K/Akt pathway is frequently active in T-ALL cells but with very heterogeneous patterns, that pan-PI3K and γ-specific inhibitors can efficiently suppress biochemical activation of Akt in T-ALL cells, and that combination therapy including PI3K inhibition is a promising direction but requires high-resolution investigations to reveal mechanistic insights in order to bring these treatment strategies into the clinic
Summary
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer characterized by abnormal growth and proliferation of early T cell progenitors. T-ALL affects children and adults, and despite substantial progress with modern chemotherapy, the prognosis remains poor for patients who relapse. The 5-year overall survival rate is approximately 80% for children with T-ALL and 45% for adults [1]. Modern treatment regimens consist of polychemotherapy with cytotoxic and genotoxic drugs that both cause substantial acute toxicity and are associated with a variety of late adverse health effects [2]. More specific and less toxic therapies are desired to improve disease outcomes and quality of life both during and after treatment. One attractive strategy for achieving this goal is to target aberrant signal transduction pathways that drive the growth and survival of leukemic blasts
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