title: 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.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gusscott
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Jenkins
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Sonya H
authors.initials: SH
authors.lastname: Lam
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giambra
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004149:Dioxoles / Q000494:pharmacology; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D004149:Dioxoles; D015851:Interleukin-7; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D045162:Thiazolidinediones; D014227:Triazines; C505145:5-(2,2-difluorobenzo(1,3)dioxol-5-ylmethylene)thiazolidine-2,4-dione; C545990:BMS 754807; C508605:IL7 protein, human; C494929:PTEN protein, human; C525021:figitumumab