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- Title
Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement.
- Authors
Kwon, Ji-Hyun; Kim, Kui-Jin; Sung, Ji Hea; Suh, Koung Jin; Lee, Ji Yun; Kim, Ji-Won; Kim, Se Hyun; Lee, Jeong-Ok; Kim, Jin Won; Kim, Yu Jung; Lee, Keun-Wook; Kim, Jee Hyun; Bang, Soo-Mee; Kim, Soyeon; Yoon, Sung-Soo; Lee, Jong Seok
- Abstract
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.
- Subjects
NON-small-cell lung carcinoma; CANCER cells; DRUG resistance in cancer cells; CELL lines; CELL cycle; MICROTUBULES
- Publication
Cells (2073-4409), 2019, Vol 8, Issue 12, p1538
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells8121538