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EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models

Medical Oncology volume 32, Article number: 205 (2015) Cite this article

Abstract

Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial.

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Acknowledgments

The study was supported by Thelma Mäkikyrö Foundation and Sigrid Juselius Foundation. We wish to thank Anne Bisi for her technical assistance.

Conflict of interest

Authors’ declare no conflict of interest.

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Affiliations

  1. Department of Medical Oncology and Radiotherapy, Oulu University Hospital, PB22, 90029, Oulu, Finland

    Niina Laurila & Jussi P. Koivunen

  2. Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland

    Niina Laurila & Jussi P. Koivunen

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  1. Niina Laurila
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  2. Jussi P. Koivunen
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Correspondence to Jussi P. Koivunen.

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Laurila, N., Koivunen, J.P. EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models. Med Oncol 32, 205 (2015). https://doi.org/10.1007/s12032-015-0627-6

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  • DOI: https://doi.org/10.1007/s12032-015-0627-6

Keywords

  • NSCLC
  • EGFR mutant
  • Tyrosine kinase inhibitor
  • Acquired resistance
  • Chemotherapy