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Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement

1
Translational Medicine, Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul 03080, Korea
2
Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Korea
3
Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam 13620, Korea
4
Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
5
Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
6
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
*
Author to whom correspondence should be addressed.
These authors have contributed equally.
Cells 2019, 8(12), 1538; https://doi.org/10.3390/cells8121538
Received: 1 October 2019 / Revised: 21 November 2019 / Accepted: 26 November 2019 / Published: 28 November 2019
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. Conclusion: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance. View Full-Text
Keywords: pemetrexed; drug resistance; afatinib; lung cancer; EML4-ALK rearrangement pemetrexed; drug resistance; afatinib; lung cancer; EML4-ALK rearrangement
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Kwon, J.-H.; Kim, K.-J.; Sung, J.H.; Suh, K.J.; Lee, J.Y.; Kim, J.-W.; Kim, S.H.; Lee, J.-O.; Kim, J.W.; Kim, Y.J.; Lee, K.-W.; Kim, J.H.; Bang, S.-M.; Kim, S.; Yoon, S.-S.; Lee, J.S. Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement. Cells 2019, 8, 1538.

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