Oncotarget

Research Papers:

Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer

Song Yi Bae, Ji-Young Hong, Hye-Jung Lee, Hyen Joo Park and Sang Kook Lee _

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Oncotarget. 2015; 6:10146-10160. https://doi.org/10.18632/oncotarget.3380

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Abstract

Song Yi Bae1, Ji-Young Hong1, Hye-Jung Lee1, Hyen Joo Park1, Sang Kook Lee1

1College of Pharmacy, Seoul National University, Seoul 151–742, Korea

Correspondence to:

Sang Kook Lee, e-mail: [email protected]

Keywords: AXL, EGFR-TKI resistance, NSCLC, PS-RIP, yuanhuadine

Received: December 14, 2014     Accepted: February 14, 2015     Published: February 26, 2015

ABSTRACT

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, remains a major problem in non-small cell lung cancer (NSCLC) treatment. Increased activation of AXL has been identified as a novel mechanism for acquired resistance to EGFR-TKIs in NSCLC treatment. However, the cause of uncontrolled AXL expression is not fully understood. Here, we first demonstrate that AXL is overexpressed in an acquired gefitinib-resistant cell line (H292-Gef) as a result of slow turnover and that AXL is degraded by presenilin-dependent regulated intramembrane proteolysis (PS-RIP). Based on the findings, we attempted to enhance AXL degradation to overcome acquired gefitinib-resistance by the treatment of gefitinib-resistant NSCLC cells with yuanhuadine (YD), a potent antitumor agent in NSCLC. Treatment with YD effectively suppressed the cancer cell survival in vitro and in vivo. Mechanistically, YD accelerated the turnover of AXL by PS-RIP and resulted in the down-regulation of the full-length AXL. Therefore, the modulation of the proteolytic process through degradation of overexpressed AXL may be an attractive therapeutic strategy for the treatment of NSCLC and EGFR-TKI-resistant NSCLC.


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