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.
Highlights
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-associated death, accounting for approximately 80–85% of all lung cancers [1, 2]
We report that the overexpression of AXL in acquired gefitinib-resistant NSCLC cells arises from the down-regulated degradation of the receptor
We demonstrate that one of the degradation mechanisms of AXL is associated with presenilindependent regulated intramembrane proteolysis (PS-RIP), and enhancing the degradation of AXL can effectively inhibit cell proliferation and tumor growth in NSCLC and EGFRTKI-resistant NSCLC cells
Summary
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-associated death, accounting for approximately 80–85% of all lung cancers [1, 2]. Acquired resistance has been observed in NSCLC patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) who initially showed an excellent response to the treatment [3]. Recent studies have reported that the overexpression of AXL correlates with resistance to EGFR-TKIs in NSCLC [6, 7]. The TAM receptors are composed of two immunoglobulin-like domains and dual fibronectin type III repeats in the extracellular region, which lead to the interaction of cells with neighboring cells, and a cytoplasmic kinase domain [8, 9]. AXL signaling is associated with cell survival, proliferation, invasion, metastasis, and anti-apoptosis [10, 11]. The activation of AXL may affect the downstream phosphoinositide 3-kinase (PI3K)/AKT, signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling pathways [12,13,14]
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