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Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118: 2609-2619

Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 08/2008; 118(7):2609-19. DOI: 10.1172/JCI34588
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ABSTRACT Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.

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Available from: Marta Guix, Jan 22, 2014
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    • "The two major mechanisms for the development of resistance during treatment are the occurrence of tumour cell clones which carry additional EGFR mutations or additional genetic alterations that can co-occur with EGFR-activating mutations (Lin and Bivona 2012). The latter include amongst others mutations in key molecular switches that control the activity of the PI3K/Akt pathway, insulin-like growth factor-1 receptor signalling or NF-κB signalling (Engelman and Settleman 2008; Guix et al. 2008; Sequist et al. 2011). "
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    Archiv für Experimentelle Pathologie und Pharmakologie 03/2014; 387(6). DOI:10.1007/s00210-014-0967-3 · 2.36 Impact Factor
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    • "For example, in EGFR mutant lung cancers that are resistant via MET amplification, combined EGFR and MET inhibition is required to suppress downstream PI3K/AKT and MEK/ERK and induce tumor regressions in vivo (Turke et al., 2010). In similar examples of resistance mediated by IGF-IR and AXL, inhibition of the bypass RTK in combination with the EGFR is needed to overcome resistance (Cortot et al., 2013; Guix et al., 2008; Zhang et al., 2012). Thus, one central strategy involving combinations centers on maintaining potent inhibition mutant EGFR while adding different inhibitors to these accessory pathways. "
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    • "In the presence of gefitinib, PI3K signalling can be maintained by an activated IGF1R pathway (Jones et al., 2006; Guix et al., 2008). Therefore it could be suggested that for single-agent anti-EGFR therapy to be effective in EGFR wildtype ovarian cancers, it would require cells to have EGFRdominant HER signalling in the absence of IGFR signalling pathways. "
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    ABSTRACT: Background: The epidermal growth factor receptor (EGFR) is expressed in ovarian cancer, but agents targeting this pathway have shown little effect as single agents. This may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway. Methods: We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the EGFR inhibitors erlotinib and gefitinib in ovarian cancer primary cell cultures. Results: The single-agent EGFR inhibitors showed little activity, although some activity was seen with the single-agent PI3K inhibitor, ZSTK474. Combinations of ZSTK474 with EGFR inhibitors showed enhanced activity with some evidence of synergy, whereas sirolimus combinations were less active. The results were not explicable on the basis of PIK3CA mutation or amplification, or PTEN loss, although one tumour with a KRAS mutation showed resistance to EGFR inhibitors. However, there was correlation of the EGFR expression with sensitivity to EGFR and resistance to PI3K active agents, and inverse correlation in the sensitivity of individual tumours to agents active against these pathways, suggesting a mechanism of action for the combination. Conclusion: Phase I/II clinical trials with these agents should include further pharmacodynamic endpoints and molecular characterisation to identify patients most likely to benefit from this strategy.
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