Abstract
BackgroundDespite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. The type I insulin-like growth factor receptor (IGF-IR) has emerged as a potential target for lung cancer treatment, however, clinical trials to date have provided disappointing results. Further research is needed to identify if certain patients would benefit from IGF-IR targeted therapies and the ideal approach to incorporate IGF-IR targeted agents with current therapies.MethodsThe dual IGF-IR/insulin receptor inhibitor, BMS-754807, was evaluated alone and in combination with platinum-based chemotherapeutics in two human non-small cell lung cancer (NSCLC) cell lines. Cell survival was determined using WST-1 assays and drug interaction was evaluated using Calcusyn software. Proliferation and apoptosis were determined using immunofluorescence for phospho-histone H3 and cleaved caspase 3, respectively.ResultsTreatment with BMS-754807 alone reduced cell survival and wound closure while enhancing apoptosis in both human lung cancer cell lines. These effects appear to be mediated through IGF-IR/IR signaling and, at least in part, through the PI3K/AKT pathway as administration of BMS-754807 to A549 or NCI-H358 cells significantly suppressed IGF-IR/IR and AKT phosphorylation. In addition of BMS-754807 enhanced the cytotoxic effects of carboplatin or cisplatin in a synergistic manner when given simultaneously to A549 cells.ConclusionsBMS-754807 may be an effective therapeutic agent for the treatment of NSCLC, particularly in lung cancer cells expressing high levels of IGF-IR.
Highlights
Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide
In A549 but not NCI-H358 cells, BMS-754807 induced synergistic cytotoxicity when combined with cisplatin or carboplatin. These findings demonstrate the benefit of inhibiting IGF-insulin receptor (IR)/IR signaling in a pre-clinical setting and suggest inhibiting IGF-IR/IR signaling should be further evaluated as a potential therapeutic strategy for the treatment of non-small cell lung cancer (NSCLC)
IGF‐IR Activity is Inhibited by BMS‐754807 A549 and NCI-H358 cells were treated with the dual IGF-IR/IR inhibitor BMS-754807 under regular growth conditions
Summary
Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. High IGF-1 and low IGFBP-3 have been associated with poor outcome [33,34,35,36,37,38,39] This suggests that increased activation of the IGF axis contributes to lung cancer progression; targeting the receptor would be an effective therapeutic strategy. Activation of the IGF-axis via the IGF-IR has been identified as a mechanism of resistance to EGFR targeted therapies [40,41,42,43,44,45] and to cisplatin [46,47,48]
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