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           Search results for: BMS-754807 Mechanisms: IGF-1R inhibitor   

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#27532210   2016/08/18 Save this To Up

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

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.

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Epidermal Growth Factor ( Epidermal Growth Factor ( Human Platelet Derived Gr Human Platelet Derived Gr Human Stromal Cell-Derive RABBIT ANTI HUMAN SDF-1 A thymic dendritic cell-der AKT PKB Signaling Phospho IGF-1R Signaling Phospho- T-Cell Receptor Signaling Growth Factor (Human) Ant Human T Cell Receptor Sig

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#23047891   2012/12/11 Save this To Up

BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor, enhances gemcitabine response in pancreatic cancer.

Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC. The therapeutic potential of BMS-754807, a small-molecule inhibitor of IGF-type 1 receptor (IGF-1R) and insulin receptor (IR), and gemcitabine was evaluated in experimental PDAC. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were conducted in murine xenografts. PDAC cells expressed phospho-IGF-1R protein. BMS-754807 and gemcitabine inhibited cell proliferation of PDAC cells; the combination of BMS-754807 with gemcitabine had additive effects. Addition of BMS-754807 decreased gemcitabine IC₅₀ from 9.7 μmol/L to 75 nmol/L for AsPC-1, from 3 μmol/L to 70 nmol/L for Panc-1, from 72 to 16 nmol/L for MIA PaCa-2, and from 28 to 16 nmol/L for BxPC-3 cells. BMS-754807 caused a decrease in phospho-IGF-1R and phospho-AKT proteins in AsPC-1 and Panc-1 cells. BMS-754807 and gemcitabine caused an increase in PARP-1 and caspase-3 cleavage. Net tumor growth inhibition in BMS-754807, gemcitabine, and BMS-754807+gemcitabine groups was 59%, 35%, and 94% as compared with controls. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BMS-754807 also caused a decrease in phospho-IGF-1R and phospho-AKT in tumor tissue lysates. Median animal survival (controls: 21 days) with BMS-754807 was 27 days (P = 0.03), with gemcitabine 28 days (P = 0.05), and in the BMS-754807+gemcitabine combination group, 41 days (P = 0.007). The strong antitumor activity of BMS-754807 in experimental PDAC supports the potential of BMS-754807-induced mechanisms for clinical PDAC therapy.

1314 related Products with: BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor, enhances gemcitabine response in pancreatic cancer.

IGF-1R Signaling Phospho- Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep

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#21220496   2011/01/11 Save this To Up

Drug efflux by breast cancer resistance protein is a mechanism of resistance to the benzimidazole insulin-like growth factor receptor/insulin receptor inhibitor, BMS-536924.

Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism.

1138 related Products with: Drug efflux by breast cancer resistance protein is a mechanism of resistance to the benzimidazole insulin-like growth factor receptor/insulin receptor inhibitor, BMS-536924.

IGF-1R Signaling Phospho- Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep Rabbit Anti-Insulin Recep

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#20807811   2010/09/16 Save this To Up

Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model.

Agents targeting insulin-like growth factor-I receptor (IGF-IR), including antibodies and small-molecule inhibitors, are currently in clinical development for the treatment of cancers including sarcoma. However, development of resistance is a common phenomenon resulting in failures of anticancer therapies. In light of this problem, we developed two resistant models from the rhabdomyosarcoma cell line Rh41: Rh41-807R, with acquired resistance to BMS-754807, a small-molecule dual-kinase inhibitor targeting IGF-IR and insulin receptor (IR), and Rh41-MAB391R, with resistance to MAB391, an IGF-IR-blocking antibody. In addition, tumor xenograft models were established from Rh41 and Rh41-807R cell lines. Gene expression and DNA copy number analyses of these models revealed shared as well as unique acquired resistance mechanisms for the two types of IGF-IR inhibitors. Each resistant model used different signaling pathways as a mechanism for proliferation. Platelet-derived growth factor receptor α (PDGFRα) was amplified, overexpressed, and constitutively activated in Rh41-807R cells and tumors. Knockdown of PDGFRα by small interfering RNA in Rh41-807R resensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with PDGFRα inhibitors in the Rh41-807R model in vitro. In contrast, AXL expression was highly elevated in Rh41-MAB391R but downregulated in Rh41-807R. Notably, BMS-754807 was active in Rh41-MAB391R cells and able to overcome resistance to MAB391, but MAB391 was not active in Rh41-807R cells, suggesting potentially broader clinical activity of BMS-754807. This is the first study to define and compare acquired resistance mechanisms for IGF-IR-targeted therapies. It provides insights into the differential acquired resistance mechanisms for IGF-IR/IR small-molecule inhibitor versus anti-IGF-IR antibody.

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IGF-1R Signaling Phospho- Growth Factor (Human) Ant FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu Interferon-a Receptor Typ interleukin 17 receptor C TGF beta induced factor 2 Protease Inhibitor 15 ant Proteasome inhibitor PI31 Recombinant Human Interfe

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