Abstract
Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and yet its acquired resistance mechanism is not clearly understood. We found that AXL is involved in both gefitinib and osimertinib resistance using in vitro and in vivo model. In addition, AXL overexpression was correlated with extended protein degradation rate. We demonstrate targeting AXL degradation is an alternative route to restore EGFR-TKIs sensitivity. We confirmed that the combination effect of YD, an AXL degrader, and EGFR-TKIs can delay or overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells, xenograft tumors, and patient-derived xenograft (PDX) models. Therefore, combination of EGFR-TKI and AXL degrader is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC.
Highlights
Epidermal growth factor receptor (EGFR) mutation is one of the major driver oncogenes in non-small cell lung cancer (NSCLC) and most frequently found in Asian patients[1,2,3]
We further demonstrated the combining YD, an AXL degrader, and EGFR-tyrosine kinase inhibitors (TKIs) resulted in overcoming resistance in EGFR-TKIs resistant NSCLC cells delaying the emergence of resistance in EGFRTKI sensitive NSCLC cells using tumor xenograft, and patient-derived xenograft (PDX) model
To investigate the molecular mechanism of EGFR-TKIs resistance, we primarily evaluated the effects of gefitinib and osimertinib, the first and third generation of EGFRTKIs, respectively, on growth of EGFR-mutant NSCLC cell lines after 72 h of treatment (PC9, PC9-gef, HCC827, HCC827-gef, HCC827-osi) (Fig. 1a)
Summary
Epidermal growth factor receptor (EGFR) mutation is one of the major driver oncogenes in non-small cell lung cancer (NSCLC) and most frequently found in Asian patients[1,2,3]. The first generation of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have led to improved prognoses for NSCLC patients, their long-term efficacy is questionable due to the emergence of acquired resistance within a year of treatment[4,5]. C797S triple mutation of EGFR, alternative approaches to control resistance are needed and the use of drug combinations may benefit patients who do not respond to current treatment[7,8]. AXL is a receptor tyrosine kinase that belongs to the TAM family which consists of three members: Tyro[3], MERTK, and AXL9. Among three TAM member, AXL, both growth arrest-specific gene 6
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