Abstract A153: Mechanisms of acquired resistance to an IGF‐1R inhibitor in multiple models
MOLECULAR CANCER THERAPEUTICS(2009)
摘要
Background: The IGF‐1R pathway plays a major role in cancer cell proliferation, survival and resistance to anti‐cancer therapies in many human malignancies. Targeting IGF‐1R represents a promising strategy in the development of novel anti‐cancer therapeutics. BMS‐754807, a small molecule inhibitor targeting both IGF‐1R/IR, demonstrated anti‐tumor activity pre‐clinically in multiple tumor types, and is currently in clinical development. A general concern in the clinic with antitumor agents is the development of resistance. In light of this problem, we have developed and characterized cell line models with acquired resistance to BMS‐754807, and identified potential mechanisms and biomarkers for the resistance. Methods: Five cell lines of different tumor types, MCF7, Rh41, Rh1, Geo and SW480 (breast, sarcomas and colon), were induced to develop acquired resistance to BMS‐754807 (range from 5‐ to 38‐fold increased resistance) by stepwise exposure to increasing concentrations of the drug for extended periods. Analyses of in vitro and in vivo drug response, gene expression profiles, signaling pathways and gene copy numbers were performed to characterize the resistant models and the corresponding sensitive parental cells. Results: Cell line specific as well as shared molecular alterations were observed in the different resistant cells using genomic approaches to define mechanisms of resistance to BMS‐754807. The resistant models were also tested against multiple IGF‐1R inhibitors and showed cross‐resistance suggesting common mechanisms of resistance to IGF‐1R inhibition. This presentation will focus on results from the MCF7‐807R model. MCF‐807R cells showed a 5‐fold decrease in IGF‐1R and > 200‐fold increase in IGFBP3 RNA expression levels, as well as overexpression of other growth receptors, such as EGFR, with > 70‐fold increase in both protein and RNA levels compared to the sensitive parental cells. MCF7‐807R and the parental MCF7 cells had differential response to inhibitors of IGF1‐R and EGFR by preferential inhibition of pAKT and pERK. When tested in vitro, MCF7‐807R cells became more sensitive than the parental to multiple EGFR inhibitors presumably due to overexpression of EGFR and growth‐dependence on EGFR; an in vivo xenograft study showed dose‐dependent tumor growth inhibition with cetuximab treatment, whereas the growth of MCF7 parental tumor xenografts was not inhibited by cetuximab. Conclusion: EGFR plays a critical role in resistance to IGF‐1R inhibition; resistant cells and tumors utilized the EGFR pathway to escape growth inhibition. Crosstalk between IGF‐1R and EGFR can confer acquired resistance to IGF‐1R inhibition through compensatory mechanisms by the enhanced activity of the reciprocal EGFR pathway. Dual EGFR and IGFR inhibition may prevent or reverse resistance to IGFR inhibitors offering a promising strategy for exploration in clinical studies to yield greater anticancer activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A153.
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abstract a153,resistance
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