ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors

• Published in: Cancer letters Vol. 328; no. 1; pp. 144 - 151
• Main Authors: Huang, Cheng-Po, Tsai, Meng-Feng, Chang, Tzu-Hua, Tang, Wei-Chien, Chen, Su-Yu, Lai, Hsiao-Hsuan, Lin, Ting-Yu, Yang, James Chih-Hsin, Yang, Pan-Chyr, Shih, Jin-Yuan, Lin, Shwu-Bin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.01.2013; Elsevier Limited
• Subjects: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase - analysis; Aldehyde dehydrogenase 1A1; analysis; Animals; antagonists & inhibitors; Antineoplastic Agents; Antineoplastic Agents - pharmacology; Cancer stem cell; Cancer therapies; cell culture; Cell Line, Tumor; chemistry; Chemotherapy; drug effects; Drug resistance; Drug Resistance, Neoplasm; drug therapy; drugs; Epidermal growth factor; epidermal growth factor receptors; ErbB Receptors; Flow cytometry; Gefitinib resistance; Gene amplification; Gene expression; Hematology, Oncology and Palliative Medicine; Humans; Kinases; Lung cancer; lung neoplasms; Lung Neoplasms - drug therapy; Male; Medical prognosis; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neoplastic Stem Cells; Neoplastic Stem Cells - chemistry; Neoplastic Stem Cells - drug effects; pharmacology; Protein Kinase Inhibitors; Protein Kinase Inhibitors - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Rodents; Stem cells; Studies; tyrosine; Tyrosine kinase inhibitor; Cancer stem cell; Aldehyde dehydrogenase 1A1; Tyrosine kinase inhibitor; Lung cancer; Gefitinib resistance
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2012.08.021

► ALDH1A1-positive lung cancer cells display significant resistance to EGFR-TKI. ► ALDH1A1-positive population is enriched in EGFR TKI resistance lung cancer cells. ► Clinical studies are consistent with results from cell culture model systems. ► We report that cancer stem cells confer resistance to EGFR TKI in lung cancer. Molecular targeting therapeutics, such as EGFR tyrosine kinase inhibitors (TKIs), are important treatment strategies for lung cancer. Currently, the major challenge confronting targeted cancer therapies is the development of resistance. Cancer stem cells (CSCs) represent a rare population of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance and spreading. Resistance to conventional chemotherapeutic drugs is a common characteristic of CSCs. However, the issue of whether CSCs contribute to EGFR TKI resistance in lung cancer is yet to be established. In the current study, we explored the association of ALDH1A1 expression with EGFR TKI resistance in lung cancer stem cells. ALDH1A1-positive lung cancer cells displayed resistance to gefitinib, compared to ALDH1A1-negative lung cancer cells. Moreover, PC9/gef cells (gefitinib-resistant lung cancer cells) presented a higher proportion of ALDH1A1-positive cells, compared to PC9 cells (gefitinib-sensitive lung cancer cells). Clinical sample studies were consistent with results from cell culture model systems showing that lung cancer cells with resistance to EGFR TKI and chemotherapy drugs contain significantly increased proportions of ALDH1A1-positive cells. These findings collectively suggest that ALDH1A1 positivity in cancer stem cells confers resistance to EGFR TKI in lung cancer.