IGF1R Derived PI3K/AKT Signaling Maintains Growth in a Subset of Human T-Cell Acute Lymphoblastic Leukemias

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.

Placenta‐specific 1 regulates oocyte meiosis and fertilization through furin

“…The newly translated IGF1R exists as the IGF1R precursor, and furin-mediated cleavage of pro-IGF1R into a shorter, active form is a prerequisite for its autophosphorylation and subsequent kinase activation in mitotic cells (31), and furin inhibition specifically abrogated IGF1-induced antiapoptosis (32). Processing of IGF1R by furin is also essential for trophoblast syncytialization (33), and IGF1R has been characterized as primarily mediating the downstream PI3K/Akt signal pathway to promote growth and survival (18,19,(34)(35)(36). In our study, we did find that both Plac1 knockdown and furin inhibition significantly reduced active IGF1R, and that IGF1R repression dramatically reduced p-Akt level.…”

Advances in studies of tyrosine kinase inhibitors and their acquired resistance

“…The IGF-1R is overexpressed in many tumors, making the proto-oncogene transcription and translation, and promoting tumor cell growth [ 132 ]. IGF-1R activates both RAS/RAF/MAPK and PI3K signaling pathways [ 133 ]. In the study of cell lines, IGF-1R leads to EGFR-TKI resistance by regulating the metabolism, proliferation and apoptosis of tumor cells and continuously activating the PI3K-AKT signaling pathway.…”

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

“…Aberrant signals originating from RTKs have been implicated in PI3K/Akt/mTOR upregulation in T-ALL. A well-documented example is increased IGF1/IGF1 receptor (IGF1R) activity [ 81 ]. Indeed, IGF1R levels are increased both transcriptionally [ 82 , 83 ] and post-transcriptionally [ 84 ] by NOTCH1 in T-ALL cells [ 46 ].…”