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Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells

Yaqiong Tian*1, Zengli Zhang†1, Liyun Miao*, Zhimin Yang, Jie Yang*, Yinhua Wang§, Danwen Qian, Hourong Cai*, Yongsheng Wang*

* Department of Respiratory Medicine, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
† Department of Respiratory Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China
‡ Department of Medical Oncology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
§ Department of Oncology, Wuhu No.2 People’s Hospital, Wuhu, Anhui Province, China
¶ Department of Oncology, Nanjing Red Cross Hospital, Nanjing, Jiangsu Province, China
1 These authors provided equal contribution to this work.

Oncology Research 2016, 24(5), 295-303. https://doi.org/10.3727/096504016X14648701447814

Abstract

Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized nonsmall cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling pathways with EGFR, such as PI3K/AKT and MAPK/ERK. AXL overexpression in resistant tumors has been implicated in many previous studies in vitro and in vivo. In this study, we further examined whether expression of AXL and its downstream targets increased in gefitinib-resistant PC9 cells (PC9GR). In addition, we hypothesize that knocking down AXL in PC9GR and overexpressing AXL in PC9 using genetic tools can restore and decrease the sensitivity to gefitinib, respectively. We found that silencing AXL could sensitize the resistance to gefitinib, and the downstream pathways were significantly inhibited. Interestingly, we also discovered that increased AXL expression did promote the resistance, and its downstream targets were activated accordingly. Then 69 NSCLC patients who harbored EGFR mutation were recruited to analyze the expression of AXL and the association between AXL expression and clinical characteristics. We found that 5 of the 69 patients were AXL positive (about 7%), and AXL was related to tumor differentiation and tumor size. In this study, we concluded that the molecular mechanisms of AXL mediated resistance involved in the increased activity of the PI3K/AKT and MAPK/ERK1/2 pathways, and AXL overexpression could promote resistance, but it can be weakened when AXL expression is silenced.

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APA Style
Tian, Y., Zhang, Z., Miao, L., Yang, Z., Yang, J. et al. (2016). Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells. Oncology Research, 24(5), 295-303. https://doi.org/10.3727/096504016X14648701447814
Vancouver Style
Tian Y, Zhang Z, Miao L, Yang Z, Yang J, Wang Y, et al. Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells. Oncol Res. 2016;24(5):295-303 https://doi.org/10.3727/096504016X14648701447814
IEEE Style
Y. Tian et al., "Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells," Oncol. Res., vol. 24, no. 5, pp. 295-303. 2016. https://doi.org/10.3727/096504016X14648701447814



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