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Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors

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Abstract

Purpose

H1650 non-small cell lung cancer (NSCLC) cells display primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) although they have a deletion mutation on exon 19 of the EGFR gene. We investigated the effect of inhibition of both insulin-like growth factor receptor (IGFR) and EGFR signaling considering that IGFR signaling pathway has been implicated in the development and progression with therapeutic resistance of various cancers including lung cancer.

Methods

Three human NSCLC cell lines with an EGFR mutation of PC-9, HCC827 and H1650 were used for experiment. Cell viability and proliferative activity were assessed by MTT and three-dimensional culture assay. Combination index was obtained by CalcuSyn software. The change of EGFR- and IGFR-related signals was evaluated by western blots.

Results

H1650 cells were 1,000 times more resistant to gefitinib and erlotinib than HCC827 and PC-9 cells possessing the same EGFR mutation. Phosphatase and tensin homolog loss and sustained phosphorylation of Akt in spite of treatment with gefitinib were evident only in H1650 cells. Interestingly, IGFR phosphorylation was decreased by gefitinib in HCC827 and PC-9 cells while being maintained in H1650 cells. Combined treatment with the IGFR inhibitors α-IR3 and AG1024 enhanced gefitinib-induced growth inhibition and apoptosis, and down-regulated phosphorylation of Akt, EGFR and IGFR.

Conclusion

Combined inhibition of IGFR signaling enhances the growth inhibitory and apoptosis-inducing effects of gefitinib, suggesting that this approach could be useful to overcome the primary resistance to EGFR-TKIs in lung cancer.

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Acknowledgments

We thank Sun Ah Park for expert technical assistance.

Conflict of interest statement

None.

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Authors and Affiliations

  1. Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, 215-4 Gongneung-dong, Nowon-gu, Seoul, 139-706, Korea

    Yun Jung Choi, Jin Kyung Rho, Byung-suk Jeon, Su Jin Choi, Su Cheol Park, Hye-Ryoun Kim, Cheol Hyeon Kim & Jae Cheol Lee

  2. Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, 215-4 Gongneung-dong, Nowon-gu, Seoul, 139-706, Korea

    Byung-suk Jeon & Seung Sook Lee

  3. University of Science and Technology, 113 Gwahangno, Yeseong-gu, Daejeon, 305-333, Korea

    Yun Jung Choi, Seung Sook Lee & Jae Cheol Lee

  4. Department of Internal Medicine, Kangwon National University College of Medicine, Chuncheon, Korea

    Su Cheol Park

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  1. Yun Jung Choi
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Correspondence to Jae Cheol Lee.

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Choi, Y.J., Rho, J.K., Jeon, Bs. et al. Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors. Cancer Chemother Pharmacol 66, 381–388 (2010). https://doi.org/10.1007/s00280-009-1174-7

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  • DOI: https://doi.org/10.1007/s00280-009-1174-7

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