• Cell Death Dis · May 2019

    AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells.

    • Donghwa Kim, Duc-Hiep Bach, Yan-Hua Fan, Thi-Thu-Trang Luu, Ji-Young Hong, Hyen Joo Park, and Sang Kook Lee.
    • College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, 08826, Korea.
    • Cell Death Dis. 2019 May 1; 10 (5): 361.

    AbstractAcquired 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.

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