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

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 ..... READ ARTICLE

Cells DOI:10.3390/cells8121538

Authors: Ji-Hyun Kwon, Kui-Jin Kim, Ji Hea Sung, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Soyeon Kim, Sung-Soo Yoon, Jong Seok Lee

Pre-ClinicalKirk SmithNovember 28, 2019Pemetrexed, drug resistance, afatinib, lung cancer, EML4-ALK rearrangement

Afatinib reverses ceritinib resistance (CR) in ALK/ROS1-positive non-small-cell lung cancer cell (NSCLC) via suppression of NRG1 pathway

As a member of the second generation of anaplastic lymphoma kinase (ALK) suppressors, ceritinib has considerable therapeutic effects for ALK and c-ros oncogene 1 (ROS1)-positive NSCLC cell. Nevertheless, patients inevitably develop resistance to the drug. Our research focused on the exploration of whether afatinib was able to counteract ceritinib resistance (CR) in NSCLC cells with positive ALK or ROS1.
These results demonstrated that afatinib overcame CR in NSCLC cells with positive ALK or ROS1 by inhibiting the NRG1 signaling pathway, which might be a promising therapeutic approach. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S173008

Authors: Hui Chen, Qiang Zhang, Yu Zhang, Bin Jia, Bin Zhang, Changli Wang

Pre-ClinicalKirk SmithNovember 26, 2018afatinib, ceritinib, NRG1, lung cancer, ALK/ROS1