Abstract
Insulin-like growth factor 1 receptor (IGF1R) is a prevalent signaling pathway in human cancer that supports cell growth/survival and thus contributes to aggressive biological behavior. Much work has gone into development of IGF1R inhibitors; however, candidate agents including small molecule tyrosine kinase inhibitors and blocking antibodies have yet to fulfill their promise clinically. Understanding cellular features that define sensitivity versus resistance are important for effective patient selection and anticipation of outgrowth of a resistant clone. We previously identified an important role for IGF signaling in T-cell acute lymphoblastic leukemia (T-ALL) relying primarily upon genetically defined mouse models. We present here an assessment of IGF1R dependence in human T-ALL using a broad panel of 27 established cell lines that capture a spectrum of the genetic variation that might be encountered in clinical practice. We observed that a subset of cell lines are sensitive to IGF1R inhibition and are characterized by high levels of surface IGF1R expression and PTEN positivity. Interestingly, lentiviral expression or knock-down of PTEN in PTEN-negative/positive cell lines, respectively, had limited effects on their response to IGF1R inhibition, suggesting that PTEN contributes to, but does not define IGF dependence. Additionally, we characterize downstream PI3K/AKT signaling as dominant over RAS/RAF/MEK/ERK in mediating growth and/or survival in this context. Finally, we demonstrate that IGF and interleukin-7 (IL-7) fulfill non-overlapping roles in supporting T-ALL growth. These findings are significant in that they reveal cellular features and downstream mechanisms that may determine the response of an individual patient’s tumor to IGF1R inhibitor therapy.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that has been shown to be reliant on multiple signaling pathways to maintain growth and survival
Both Insulin-like growth factor 1 receptor (IGF1R) blocking antibodies and small molecule tyrosine kinase inhibitors have met with limited success in clinical trials such that these are generally considered inactive as single agents[32, 33]
We have taken up this issue in the context of T-ALL and employed a broad screen of 27 established human T-ALL cell lines to capture a spectrum of genetic backgrounds in the disease
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that has been shown to be reliant on multiple signaling pathways to maintain growth and survival. We and others have reported previously that IGF1R is upregulated both transcriptionally[4, 14] and post transcriptionally[15] in T-ALL by NOTCH1, a prominent oncogene in the disease[1], and that IGF signaling contributes to growth/survival of bulk cells and to leukemia-initiating activity[4]. These observations suggest that pharmacologic inhibition of IGF signaling may have a therapeutic role in T-ALL, both in terms of treating bulk disease as well as in targeting leukemia stem cells to prevent relapse. We describe here that a subset of cell lines demonstrates sensitivity to these agents and characterize genetic/phenotypic features that define cellular dependence on IGF signaling
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